Individualised mindfulness-based stress reduction for head and neck cancer patients undergoing radiotherapy of curative intent: a descriptive pilot study.

People with head and neck cancer (HNC) experience elevated symptom toxicity and co-morbidity as a result of treatment, which is associated with poorer psychosocial and quality-of-life (QoL) outcomes. This Phase I study examined whether an individualised mindfulness-based stress reduction (IMBSR) programme could be successfully used with HNC patients undergoing curative treatment. Primary aims were to explore feasibility, compliance, acceptability and fidelity. Secondary aims were to determine whether (1) participation in the intervention was associated with changes in post-intervention mindfulness and (2) post-intervention mindfulness was associated with post-intervention distress and QoL. Nineteen HNC patients participated in a seven-session IMBSR programme with pre- and post-test outcome measures of psychological distress, depression, anxiety and QoL. Primary aims were assessed by therapists or participants. Mindfulness, distress and QoL were assessed using self-report questionnaires at pre- and post-intervention. Longer time spent meditating daily was associated with higher post-intervention mindfulness. After controlling for pre-intervention mindfulness, there was an association between higher post-intervention mindfulness and lower psychological distress and higher total, social and emotional QoL. This study offers important preliminary evidence than an IMBSR intervention can be administered to HNC patients during active cancer treatment. A randomised controlled trial is warranted to confirm these findings.

Use of trifluoroacetic acid to quantify small, polar compounds in rat plasma during discovery-phase pharmacokinetic evaluation.

Although it is accepted that trifluoroacetic acid (TFA) can cause suppression of an analyte during LC/MS analysis, this paper presents a relatively sensitive gradient method that uses a TFA mobile phase for the improved quantification of small, polar drug-like compounds. The described method was developed in a discovery drug metabolism and pharmacokinetics (DMPK) laboratory for the screening measurement of compound concentrations to calculate PK parameters and CNS exposure of compounds from a chemical series that had poor chromatography under generic methods using formic acid mobile phase. The samples were collected by a Culex automated sampling unit, and the plasma proteins were precipitated by a Tecan robot in 96-well plates. After centrifugation, the supernatant was removed, dried down using a SPE-Dry unit, and the samples were reconstituted in aqueous buffer on the robot. The samples were analyzed on an Agilent LC/MSD using a 5-min gradient on a 5 cm phenyl column. No additional steps, such as the "TFA-fix", were necessary. Although sample batches were analyzed over 6h, no drift or degradation of signal was observed. The improved chromatography resulted in a method that was selective, rugged, and had a dynamic range from 5 to 20,000 nM, which was sufficient to quantitate low volume, serial plasma samples collected out to 8 h postdose.

The contribution of visual search strategies to the development of pedestrian skills by 4-11 year-old children.

BACKGROUND: Young children in the 5-9 age range are particularly vulnerable to road accidents as pedestrians and previous research has identified a range of motivational and cognitive skill factors which may play a part in this. AIMS: The present study aimed to examine the extent to which the development of pedestrian skills in young children was related to individual differences in visual search strategies. SAMPLE: A sample of 180 children aged 4/5, 7/8 and 10/11 years was presented with tasks intended to assess their pedestrian skills. From this analysis a subset of 60 children was selected who had particularly high or low levels of pedestrian skills, together with a random sample of 10 adults, for more detailed analysis of their visual search strategies when confronted with the problem of crossing a road safely. METHOD: The children's pedestrian skills were assessed using three tasks based on slide and video presentations of real roadside situations; these tasks assessed the ability to identify safe places to cross the road, and to decide when it was safe to cross based on the ability to detect dangerous traffic and to co-ordinate information from different directions. Visual search strategies were assessed using a 'spot the difference' test and by analysing the head and eye movements of children and adults while they were carrying out the video task requiring them to co-ordinate information from different directions. This task was also used to make an assessment of individuals' processing speeds by measuring the time it took to make decisions that it was safe to cross the road. RESULTS: Significant differences emerged in strategic approaches between children in different age groups, and those who had high and low levels of pedestrians skills. A significant strategic shift appeared to be occurring around the age of 7/8 years. CONCLUSIONS: The results indicate that the explicit training of visual search strategies might well be beneficial, but that these cannot simply be the strategies of the adult pedestrian. Children may need to master simpler strategies which their slower processing speeds allow them to manage before they proceed on to the more sophisticated strategic approaches, typically involving predictions, used by older children and adults.

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains.

The fibroblast growth factor receptors (FGFRs) are a family of receptor protein tyrosine kinases that have been shown to mediate a variety of cellular processes including angiogenesis, wound healing, tumorigenesis, and embryonic development. Distinct FGFR mutations in individuals with autosomal dominant disorders of bone growth and development provide a unique opportunity to determine the function of FGFRs during embryonic development. To determine the consequences of these mutations on receptor function, we have made mutations in Xenopus FGFR1 (XFGFR1) and FGFR2 (XFGFR2) that correspond to several of the mutations identified in these dysmorphic syndromes. Analysis of mutant receptor proteins expressed in Xenopus oocytes indicates that all but one have elevated tyrosine kinase activity relative to their wild-type counterparts. Those mutations that give an unpaired cysteine residue in the extracellular domain result in intermolecular disulfide bond formation and covalent receptor dimerization. Microinjection of Xenopus embryos with RNA encoding mutant receptors with elevated tyrosine kinase activity results in ligand-independent induction of mesoderm in animal pole explants. Wild-type XFGFR1 and XFGFR2 do not induce mesoderm when injected at similar doses. Co-injection of RNA encoding a dominant negative FGF receptor, lacking the tyrosine kinase domain, together with RNA encoding various activated FGFRs inhibits mesoderm induction by a receptor activated by a transmembrane domain mutation or extracellular mutations that introduce an unpaired cysteine residue into the extracellular domain but does not inhibit mesoderm induction by receptors bearing a tyrosine kinase domain mutation. These results indicate that different point mutations may activate FGFRs by distinct mechanisms and that ligand-independent FGFR activation may be a feature in common to many skeletal disorders.

Constitutive activation of fibroblast growth factor receptor-2 by a point mutation associated with Crouzon syndrome.

The fibroblast growth factor receptors (FGFRs) are a family of ligand-activated, membrane-spanning tyrosine kinases. Mutations in several human FGFR genes have been identified as playing a role in certain disorders of bone growth and development. One of these, Crouzon syndrome, an autosomal dominant disorder causing craniosynostosis, has been associated with mutations in the human FGFR-2 gene. We report here that microinjection of Xenopus embryos with RNA encoding an FGFR-2 protein bearing a Cys332-->Tyr mutation (FGFR-2CS) found in Crouzon syndrome results in fibroblast growth factor (FGF)-independent induction of mesoderm in animal pole explants. Wild-type FGFR-2 did not induce mesoderm when injected at similar doses. The effects of the mutant receptor were blocked by co-expression of dominant negative mutants of either Raf or Ras. Analysis of the mutant receptor protein expressed in Xenopus oocytes indicates that it forms covalent homodimers, does not bind radiolabeled FGF, and has increased tyrosine phosphorylation. These results indicate that FGFR-2CS forms an intermolecular disulfide bond resulting in receptor dimerization and ligand-independent activation that may play a role in the etiology of Crouzon syndrome.

Congenital generalized myofibromatosis: a disseminated angiocentric myofibromatosis.

Infantile myofibromatosis occurs in solitary, multiple, and generalized forms, with similar histology but different clinicopathologic and prognostic implications. We report the findings in two male infants with fatal congenital generalized myofibromatosis (CGMF) who presented with multiple dermal and subcutaneous nodules at birth. Imaging studies revealed bony and visceral lesions, which progressed despite chemotherapy. One infant had severe hypercalcemia associated with extensive lytic bone lesions. Both infants died in respiratory failure and had a combination of pulmonary CGMF and diffuse alveolar damage. Involvement of skin, soft tissue, bone, heart, lungs, liver, gastrointestinal tract, and endocrine organs was confirmed at autopsy in each case. A consistent histologic pattern of interlacing fascicles of myofibroblasts with abundant eosinophilic cytoplasm was noted, with variable necrosis and calcifications in some sites. The myofibroblasts displayed vimentin and smooth muscle actin immunoreactivity. The lungs in each case had the presumably early lesions of CGMF with an angiocentric and perivascular growth of myofibroblasts. A similar vascular pattern was present in all affected organs. These two cases demonstrate the extraordinary presentation of CGMF, which suggests its multifocal origin from vascular subintimal mesenchymal or smooth muscle cells whose phenotype is that of myofibroblasts.

Structure of the human cyclo-oxygenase-2 gene.

Cyclo-oxygenase (Cox), a rate-limiting enzyme in the synthesis of prostanoids, is encoded by two genes, Cox-1 and Cox-2, which are differentially expressed and regulated. Human Cox-1 and -2 polypeptides share 61% primary sequence identity. While the expression of Cox-1 is maximal in quiescent cells. Cox-2 expression is induced by growth factors and cytokines. We have screened a human genomic library with a probe from the 5'-untranslated region (UTR) of the human Cox-2 (hCox-2) cDNA and isolated two overlapping genomic clones. We have determined the DNA sequence of 0.8 kb upstream of the transcription start site, 6 kb of protein coding region, which includes 10 exons and 9 introns, as well as 2.5 kb of the 3'-UTR. The structures of the hCox-1 and hCox-2 and the murine TIS10 (Cox-2) genes are highly conserved, with a few exceptions. The 3'-UTRs of the Cox-1 and -2 genes are distinct; for example, the largest exon in the Cox-2 gene encodes the entire 3'-UTR, containing 22 copies of the 'AUUUA' RNA instability element. Sequence analysis of the 5'-flanking region has shown several potential transcription regulatory sequences, including a TATA box, a C/EBP motif, two AP-2 sites, three SP1 sites, two NF-kappa B sites, a CRE motif and an Ets-1 site. These efforts serve as a basis for future studies on transcriptional and post-transcriptional mechanisms of Cox-2 gene regulation.

Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis.

Neonatal liver failure was evaluated in two infants. Neither infant had evidence of congenital infection, galactosemia, alpha 1-antitrypsin deficiency, tyrosinemia, Zellweger syndrome, or hemophagocytic lymphohistiocytosis. Abnormal levels of iron were detected in the minor salivary glands of the first infant and in the explanted liver of the second. Analyses of urinary bile salts by fast-atom bombardment ionization mass spectrometry and gas chromatography-mass spectrometry revealed a paucity of primary bile acids and a predominance of 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids. These findings are consistent with delta 4-3-oxosteroid 5 beta-reductase deficiency, a primary genetic defect in bile acid synthesis. Postmortem evaluation of the first infant revealed significant iron deposition in the liver, pancreas, thyroid, adrenal glands, myocardium, stomach, and submucosal glands of the respiratory tract. In both infants examination of the liver revealed extensive loss of hepatic parenchyma. These cases expand the clinical spectrum of bile acid metabolism defects to include neonatal liver failure with associated hemochromatosis.

Trigeminal neuralgia: a cautionary tale.

Trigeminal neuralgia is one of the paroxysmal symptoms of multiple sclerosis and may appear in the prodromal stage of this degenerative disease. A patient is described who was diagnosed as suffering from idiopathic trigeminal neuralgia and subsequently developed symptoms of generalised neurological disease, diagnosed as multiple sclerosis. Clinicians should be cautious when diagnosing younger patients as suffering from idiopathic trigeminal neuralgia and all suspicious cases should be referred to a neurologist for full assessment.

Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes.

Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]- 3- methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a transposed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.

Primary malignant rhabdoid tumour of the liver.

The authors describe the imaging features (from radiography, ultrasonography, computed tomography and angiography) of primary malignant rhabdoid tumour of the liver in an infant. The findings were not specific, and the diagnosis of this aggressive neoplasm was based on observations obtained with electron microscopy and immunohistochemical stains.

Pseudo-trisomy 13 syndrome with upper limb shortness and radial hypoplasia.

We report on a fetus with holoprosencephaly, postaxial polydactyly, multiple visceral anomalies, upper limb shortness, and radial hypoplasia with normal chromosomes. We provide a brief review of the newly delineated "pseudo-trisomy 13 syndrome." Severe limb shortness of radial hypoplasia has not been described previously in this syndrome. The present case may expand the spectrum of the pseudo-trisomy 13 syndrome, or may represent a distinct entity.

Human cyclooxygenase-2 cDNA.

Cyclooxygenase (Cox), also known as prostaglandin (PG) H synthase (EC 1.14.99.1), catalyzes the rate-limiting step in the formation of inflammatory PGs. A major regulatory step in PG biosynthesis is at the level of Cox: growth factors, cytokines, and tumor promoters induce Cox activity. We have cloned the second form of the Cox gene (Cox-2) from human umbilical vein endothelial cells (HUVEC). The cDNA encodes a polypeptide of 604 amino acids that is 61% identical to the previously isolated human Cox-1 polypeptide. In vitro translation of the human (h)Cox-2 transcript in rabbit reticulocyte lysates resulted in the synthesis of a 70-kDa protein that is immunoprecipitated by antiserum to ovine Cox. Expression of the hCox-2 open reading frame in Cos-7 monkey kidney cells results in the elaboration of cyclooxygenase activity. hCox-2 cDNA hybridizes to a 4.5-kilobase mRNA species in HUVEC, whereas the hCox-1 cDNA hybridizes to 3- and 5.3-kilobase species. Both Cox-1 and Cox-2 mRNAs are expressed in HUVEC, vascular smooth muscle cells, monocytes, and fibroblasts. Cox-2 mRNA was preferentially induced by phorbol 12-myristate 13-acetate and lipopolysaccharide in human endothelial cells and monocytes. Together, these data demonstrate that the Cox enzyme is encoded by at least two genes that are expressed and differentially regulated in a variety of cell types. High-level induction of the hCox-2 transcript in mesenchymal-derived inflammatory cells suggests a role in inflammatory conditions.

Time-averaged accommodation response to flickering stimuli.

Experiments are described in which the steady-state accommodation response versus stimulus curve was measured with an infrared autorefractor for high-contrast stimuli having a 100% square-wave temporal modulation of luminance in the frequency band 1-200 Hz. Slightly more accurate responses were found at frequencies approximately 50-100 Hz, i.e. above flicker fusion. The relevance of the results to practical situations in which flicker may be experienced is discussed.

Cardiac fibroma presenting with clinically significant arrhythmias in infancy.

Supraventricular or ventricular ectopy has been reported in association with cardiac fibroma. We report two patients, one with acquired complete heart block and one with mixed ventricular and supraventricular arrhythmias associated with this rare tumor of the heart.

Cloning and expression of the human S100 beta gene.

S100 protein is a low molecular weight, EF-hand, Ca2(+)-binding protein widely distributed and conserved in the central nervous system of vertebrates. The gene coding for the beta subunit of human S100 protein (S100 beta) has been recently mapped to chromosome 21. In order to study the expression of this gene in normal and abnormal brain development, we have isolated and characterized overlapping genomic clones spanning the region coding for human S100 beta and its flanking sequences. The intron-exon organization of the human S100 beta gene is similar to that of the genes coding for several other members of the S100 protein subfamily of EF-hand proteins. The human S100 beta gene is composed of 3 exons, the first of which specifies the 5'-untranslated region, while the second and third each encode a single EF-hand, Ca2(+)-binding domain. The promoter region contains several potential regulatory transcription elements including the cAMP-responsive elements CRE and AP-2. A novel sequence motif, the S100 protein element, situated in close proximity to the TATA box of the genes of several members of the S100 protein subfamily, has been identified. In addition, multiple repeats with similar nucleotide sequence and location to the recently reported beta globin direct repeat elements have been also found in the human S100 beta promoter. A full length (17.3 kilobases) copy of the human S100 beta gene was constructed and transfected into rat glioma C6 cells. Stable transfectants were shown to express correctly initiated transcripts of the human S100 beta gene, indicating that the cloned sequences contain functional regulatory transcription elements.

Augmentation cystoplasty in rats: development of an animal model.

An animal model of the Long-Evans species of rats was developed to study the short-term and long-term effects of enterocystoplasty. Various enterocystoplasties were performed in 39 rats, including ileal in 29, colonic in 5 and gastric in 5. The followup period was 3 months. Frequency and pattern of voiding, 24-hour urinary collection for mucus production, and blood and urinary electrolytes were analyzed. All voiding parameters, renal function and biochemical studies remained normal. Mucus production was higher in the gastrocystoplasty and colocystoplasty than in ileocystoplasty cases. Postmortem histopathological examination of the enteropatch was performed, which showed urothelialization of the graft with native transitional epithelium extending over the junctional margin of the graft and covering the enteropatch mucosa. The enteropatch muscle orientation was maintained in all 3 types of grafts. We believe that the Long-Evans species of rats is a good model for the study of enterocystoplasty.

Demonstration of respiratory syncytial virus in an autopsy series.

Respiratory syncytial virus (RSV) antigen was demonstrated in formalin-fixed, paraffin-embedded autopsy tissue using an immunoperoxidase technique. Eighteen autopsy cases were selected on the basis of one of the following criteria: a positive culture for RSV, antemortem or postmortem; positive ELISA test for RSV, antemortem or postmortem; or postmortem histology suggestive of paramyxovirus infection. Controls included three cases from which parainfluenza or influenza virus had been cultured and a case in which the clinical diagnosis of measles was firmly established. Sections of formalin-fixed, paraffin-embedded tissue were stained with a rabbit anti-RSV antibody (Dako) using an immunoperoxidase technique. Staining was achieved in 12 cases. This included 6 of 7 cases selected because of positive cultures or ELISA tests for RSV. The other 6 cases in which RSV was identified by the described technique lacked culture or ELISA confirmation. Granular and globular staining was seen in the cytoplasm of respiratory epithelial cells and syncytial giant cells. None of the control cases stained for RSV. The histology of RSV lungs was consistent with changes described in the literature for RSV infection, although pneumonic consolidation and syncytial giant cells were more prominent in this series.

Psychometric prediction of driving performance among the disabled.

A battery of psychometric and performance tests was administered to 25 subjects who were classified into able-bodied (n = 8), brain-injured (n = 10), and spinal cord injured groups (n = 7). All disabled subjects were regarded by their referring rehabilitation therapists as potential candidates for driver assessment. Data were analyzed to identify which measures were useful in differentiating among the groups and predicting driving performance. Results indicated that psychometric measures can be useful in predicting driving performance among disabled drivers. Nearly all the measures in the battery were significant predictors of driving ability, and some were highly predictive. The best was the oral version of the Symbol Digit Modalities test, which by itself accounted for 70% of the variance of the full-sized-vehicle driving score. Adding a second variable into a two-step multiple regression further increased the correlation between predictors and driving, accounting for almost 80% of the variance in driving score. These findings support the feasibility of developing a simple test battery to determine which disabled candidates are ready for in-vehicle assessment, and which candidates are not ready without further evaluation of cognitive and performance skills.