Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF. METHODS: Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not. RESULTS: Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics. CONCLUSION: Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

On the high-pressure phase stability and elastic properties of ß-titanium alloys.

We have studied the compressibility and stability of different ß-titanium alloys at high pressure, including binary Ti-Mo, Ti-24Nb-4Zr-8Sn (Ti2448) and Ti-36Nb-2Ta-0.3O (gum metal). We observed stability of the ß phase in these alloys to 40 GPa, well into the ω phase region in the P-T diagram of pure titanium. Gum metal was pressurised above 70 GPa and forms a phase with a crystal structure similar to the η phase of pure Ti. The bulk moduli determined for the different alloys range from 97 ± 3 GPa (Ti2448) to 124 ± 6 GPa (Ti-16.8Mo-0.13O).

Predicting intrapartum fetal compromise using the fetal cerebro-umbilical ratio.

INTRODUCTION: The aim of this study was to explore the association between the cerebro-umbilical ratio measured at 35-37 weeks and intrapartum fetal compromise. METHODS: This retrospective cross sectional study was conducted at the Mater Mothers' Hospital in Brisbane, Australia. Maternal demographics and fetal Doppler indices at 35-37 weeks gestation for 1381 women were correlated with intrapartum and neonatal outcomes. RESULTS: Babies born by caesarean section or instrumental delivery for fetal compromise had the lowest median cerebro-umbilical ratio 1.60 (IQR 1.22-2.08) compared to all other delivery groups (vaginal delivery, emergency delivery for failure to progress, emergency caesarean section for other reasons or elective caesarean section). The percentage of infants with a cerebro-umbilical ratio <10th centile that required emergency delivery (caesarean section or instrumental delivery) for fetal compromise was 22%, whereas only 7.3% of infants with a cerebro-umbilical ratio between the 10th-90th centile and 9.6% of infants with a cerebro-umbilical ratio > 90th centile required delivery for the same indication (p < 0.001). A lower cerebro-umbilical ratio was associated with an increased risk of emergency delivery for fetal compromise, OR 2.03 (95% CI 1.41-2.92), p < 0.0001. DISCUSSION: This study suggests that a low fetal cerebro-umbilical ratio measured at 35-37 weeks is associated with a greater risk of intrapartum compromise. This is a relatively simple technique which could be used to risk stratify women in diverse healthcare settings.

Stabilization of boron carbide via silicon doping.

Boron carbide is one of the lightest and hardest ceramics, but its applications are limited by its poor stability against a partial phase separation into separate boron and carbon. Phase separation is observed under high non-hydrostatic stress (both static and dynamic), resulting in amorphization. The phase separation is thought to occur in just one of the many naturally occurring polytypes in the material, and this raises the possibility of doping the boron carbide to eliminate this polytype. In this work, we have synthesized boron carbide doped with silicon. We have conducted a series of characterizations (transmission electron microscopy, scanning electron microscopy, Raman spectroscopy and x-ray diffraction) on pure and silicon-doped boron carbide following static compression to 50 GPa non-hydrostatic pressure. We find that the level of amorphization under static non-hydrostatic pressure is drastically reduced by the silicon doping.

Are fetuses that fail to achieve their growth potential at increased risk of intrapartum compromise?

OBJECTIVE: The true growth potential of a fetus is difficult to predict but recently a new definition, independent of fetal weight, using cerebroplacental (cerebro-umbilical) ratio (CPR) < 0.6765 multiples of the median (MoM), was reported. We applied this definition to a cohort of low-risk pregnancies recruited prospectively to determine if fetuses with CPR < 0.6765 are at increased risk of developing signs of intrapartum fetal compromise. METHODS: Recruitment to this prospective observational study took place between March 2011 and March 2014. All women with low-risk singleton pregnancies at term were eligible. Women with known or suspected placental dysfunction were excluded, as were women with fetuses with an estimated fetal weight < 10(th) centile. All participants underwent ultrasound examination prior to active labor (≤ 4 cm cervical dilatation), during which fetal biometry as well as umbilical artery and fetal middle cerebral artery blood flow were assessed. Following delivery, intrapartum and neonatal outcomes were compared between fetuses that had a CPR < 0.6765 MoM and those that had a CPR ≥ 0.6765 MoM. RESULTS: In total, 775 women were recruited. Fetuses with CPR < 0.6765 MoM were significantly more likely to require Cesarean delivery because of presumed fetal compromise (P < 0.001). These fetuses were also at increased risk of compromise at any time during labor and were less likely to be delivered vaginally, spontaneously or otherwise, than were those with CPR ≥ 0.6765 MoM. CPR < 0.6765 MoM gave a positive predictive value (PPV) for Cesarean delivery because of presumed fetal compromise of 36.7% and a negative predictive value of 88.7%, with a sensitivity of 18% and a specificity of 95.4%. CONCLUSION: Fetuses that failed to achieve their growth potential (defined as CPR < 0.6765 MoM) were at increased risk of intrapartum compromise and were less likely to be delivered vaginally. However, a low negative predictive value was observed for fetal compromise and further studies are required to support the translation of this technique into clinical practice.

Influence of parity on fetal hemodynamics and amniotic fluid volume at term.

OBJECTIVES: Pregnancy complications, particularly those associated with placental dysfunction, occur more frequently in nulliparous than in parous women. This difference may be a consequence of improved trophoblastic invasion and, as a result, improved placental function following previous pregnancy. Placental dysfunction in cases of fetal growth restriction may be identified by ultrasound assessment of fetoplacental hemodynamics and amniotic fluid volume. In this prospective observational study, we investigated whether differences in these measures of placental function exist between nulliparous and parous women, prior to active labor. METHODS: Over a 2-year period, 456 nulliparous and 152 parous women with uncomplicated singleton pregnancies were recruited to this prospective observational study. Each participant underwent an ultrasound assessment prior to active labor, during which fetal biometry, umbilical artery, middle cerebral artery and umbilical venous Dopplers, as well as amniotic fluid volume, were assessed. All cases were followed up within 48 h of delivery. Ultrasound parameters and intrapartum outcomes were then compared between the nulliparous and parous groups. RESULTS: Compared with nulliparous women, parous women had significantly higher fetal middle cerebral artery pulsatility index, cerebroplacental ratio and amniotic fluid volume. In nulliparous women, middle cerebral artery flow rate was also significantly higher and represented a greater percentage of umbilical venous flow than was observed in parous women. CONCLUSION: Prior to the active phase of labor, ultrasound parameters indicative of placental function differ significantly between nulliparous and parous pregnancy, even amongst an uncomplicated, low-risk cohort.

Adaptive 18fluoro-2-deoxyglucose positron emission tomography/computed tomography-based target volume delineation in radiotherapy planning of head and neck cancer.

AIMS: This study investigated an adaptive threshold-based method to delineate the target volume using (18)fluoro-2-deoxyglucose ((18)FDG) positron emission tomography/computed tomography (PET/CT) before and during a course of radical radiotherapy or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Ten patients were enrolled between March 2006 and May 2008. (18)FDG PET/CT scans were carried out 72h before the start of radiotherapy and then at three time points during radiotherapy (8-18, 36-50 and 66Gy). Functional volumes were delineated using an adaptive iterative algorithm weighted according to the mean standard uptake value (SUV(mean)) within the region of interest. The background (18)FDG uptake, maximum standard uptake value (SUV(max)) and SUV(mean) within the volumes were assessed. RESULTS: There was no significant reduction in the primary target volumes defined by the adaptive threshold during radiotherapy. However, the SUV(max) significantly reduced within the primary (P=0.003-0.011) and lymph node (P<0.0001) target volume at 36-50 and 36-66Gy compared with 0Gy. The SUV(mean) was negatively correlated to radiation dose (P<0.0001-0.014). The ratio between the background uptake of (18)FDG and the SUV(mean) significantly reduced for both the lymph node target volume at 36-50Gy and the primary volume at 66Gy. The lack of significant correlation between the defined volume and radiation dose was because the SUV(mean) within the region of interest used to define the edge of the volume was equal to or less than the background (18)FDG uptake and the software was unable to effectively differentiate between tumour and background uptake. CONCLUSIONS: The adaptive threshold method may be of benefit when used to define the target volume before the start of radiotherapy. This method was not beneficial during radiotherapy because the software is not sensitive enough to distinguish tumour from background and define a volume. (18)FDG PET/CT-guided volumes delineated by automatic adaptive thresholding methods should only be used for dose escalation with the pretreatment imaging.

Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach.

OBJECTIVE: Idiopathic peripheral neuropathy is common and likely due to genetic factors that are not detectable using standard linkage analysis. We initiated a candidate gene approach to study the genetic influence of the small heat shock protein (sHSP) gene family on an axonal motor and motor/sensory neuropathy patient population. METHODS: The promoter region and all exonic and intronic sequences of the 10 sHSP genes (HSPB1-HSPB10) were screened in a cohort of presumed nonacquired, axonal motor and motor/sensory neuropathy patients seen at the Ohio State University Neuromuscular Clinic. RESULTS: A missense mutation in the gene encoding small heat shock protein B3 (HSPB3, also called HSP27, protein 3) was discovered in 2 siblings with an asymmetric axonal motor neuropathy. Electrophysiologic studies revealed an axonal, predominantly motor, length-dependent neuropathy. The mutation, HSPB3(R7S), is located in the N-terminal domain and involves the loss of a conserved arginine. CONCLUSIONS: The discovery of an HSPB3 mutation associated with an axonal motor neuropathy using a candidate gene approach supports the notion that the small heat shock protein gene family coordinately plays an important role in motor neuron viability.

A new approach to identify species in Xiphinema americanum sensu lato.

Four putative species belonging to the X. americanum group are known to transmit American nepoviruses and these nematodes and viruses are listed in European quarantine legislation. Identification of species in this group is therefore of particular importance for phytosanitary purposes, but is problematic because of the similar morphology of the putative species. As part of the Synthesys project BE-TAF 1769, eight collaborative institutions contributed material to Fera for study. Video technology allowed the best records of type material and in conjunction with photographic images created a 'virtual' collection of images that relies less on the deteriorating quality of museum specimens. Revised definitions of lip region and tail shape are considered to be the most stable characters for differentiation. Position of the amphidial aperture, development of the odontostyle collar and some established morphometric characters are considered of limited use although they retain value for latter stages of identification.

Preclinical validation of a multiplex real-time assay to quantify SMN mRNA in patients with SMA.

OBJECTIVE: To determine whether survival motor neuron (SMN) expression was stable over time. METHODS: We developed a multiplex real-time reverse transcriptase (RT)-PCR assay to quantify SMN transcripts in preclinical blood samples from 42 patients with spinal muscular atrophy (SMA) drawn for three time points per patient; most blood samples were shipped to a centralized laboratory. RESULTS: We obtained a sufficient amount (9.7 +/- 5.6 microg) of good-quality total RNA, and RNAs were stable for up to a 3-year interval. This allowed RNA samples collected during a 9- to 12-month period to be analyzed in a single run, thus minimizing interexperimental variability. SMN expression was stable over time; intersample variability for baseline measures, collected during a 17-month interval, was less than 15% for 38 of 42 SMA patients analyzed. This variability was well below the 1.95-fold increase in full-length SMN (flSMN) transcripts detected in SMA fibroblasts treated with 10 mM valproic acid. CONCLUSION: Real-time quantification of SMN messenger RNA expression may be a biomarker that is amenable to multicenter SMA clinical trials.

Diagnostic and prognostic value of glycosyltransferase mRNA in glioblastoma multiforme patients.

Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumour in adults with an average survival of 11 months. The 2-year survival is less than 10%, and only a small proportion of patients are alive at 3 years. Despite improved treatment strategies and aggressive therapy, the prognosis of GBM has changed little in past decades. Thus, any test that can reliably and rapidly diagnose the tumour and predict patient survival could be a valuable tool. Herein we report the use of quantitative real-time polymerase chain reaction (PCR) to quantify five glycosyltransferase transcripts in gliomas. Our results indicate that measuring GM1 synthase (beta-1,3 galactosyltransferase) mRNA may provide a useful method for segregating GBMs from other types of gliomas. In these studies, 97% of gliomas (36/37 tumours) below a threshold value had a diagnosis of GBM compared with 49% (52/106 tumours) above the threshold. More importantly, the increased expression of GD3 synthase mRNA in combination with decreased GalNAcT message correlated with increased survival in 79 GBM patients (proportional hazards model controlling for age, P = 0.02). These data were further corroborated by a data analysis from one of our previous studies on gangliosides of 80 GBMs, in which increased amounts of GM3 and GD3 (which accumulate in the absence of GalNAcT) correlated with a longer survival (P < 0.01). Thus, measuring GalNAcT and GD3 transcripts may provide a rapid method to assess prognosis in GBM patients. In summary, the data indicate that measuring glycosyltransferase mRNA levels by real-time PCR may be clinically useful for determining both diagnosis and prognosis in GBM patients.

Design, chirality, and flexibility in nanoporous molecule-based materials.

Scientific and technological interest in porous materials with molecule-sized channels and cavities has led to an intense search for controlled chemical routes to systems with specific properties. This Account details our work on directing the assembly of open-framework structures based on molecules and investigating how the response of nanoporous examples of such materials to guests differs from classical rigid porous systems. The stabilization of chiral nanoporosity by a hierarchy of interactions that both direct and maintain a helical open-framework structure exemplifies the approach.

Phenotypic differences in cholinergic responses of distal colonic epithelium.

The Flinders sensitive line (FSL) rats exhibit an increased cholinergic responsiveness in vivo when compared to their counterparts, the Flinders resistant line (FRL) rats. The functional consequences of this phenotypic difference on colonic mucosal function are not known. We sought to determine whether isolated distal colonic mucosa from the two strains exhibit differential responses to cholinergic agonists. The responses of the distal colonic mucosa from two lines of rats to carbachol were compared by recording changes in short-circuit current. The ion movements associated with these changes were assessed by flux analysis of the radiotracers, 22Na and 36Cl. The anticipated hyper-responsiveness to cholinergic stimulation in FSL rats was not seen. Carbachol responses were significantly enhanced by indomethacin pretreatment only in FRL rats. Tetrodotoxin (TTX) pretreatment significantly reduced responses to carbachol in FSL rats at all concentrations tested, though this was only seen with lower concentrations in FRL rats. Flux analysis indicated that both lines absorbed Na+ and Cl- under basal conditions and that a significant residual flux was present. Stimulation with carbachol led to significant reductions in net Na+ and Cl- fluxes in both lines. The changes in net Na+ and Cl- flux in both lines stem largely from a decrease in mucosal to serosal fluxes of both ions with an increase in serosal to mucosal flux of Cl-. The striking difference is the significant reduction in residual flux seen only in FRL rats. Indomethacin pretreatment abolished the changes in residual flux seen in FRL rats. Thus the responses to carbachol in these rats had at least three components: (a) a direct effect on the transporting colonocyte, (b) an indirect effect mediated by an arachidonic acid metabolite, and (c) another indirect effect involving a neurotransmitter. The relative contributions of each of these components were different in the two lines.

Interventions for treating hallux valgus (abductovalgus) and bunions.

BACKGROUND: Hallux valgus is classified as an abnormal deviation of the great toe (hallux) towards the midline of the foot. OBJECTIVES: To identify and evaluate the evidence from randomised trials of interventions used to correct hallux valgus. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group trials register (2003/1), the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2003), MEDLINE (January 1966 to March 2003) and EMBASE (1980 to January 2003). No language restrictions were applied. Hand searching of specific foot journals was also undertaken. Date of the most recent search: 31st March 2003. SELECTION CRITERIA: Randomised or quasi-randomised trials of both conservative and surgical treatments of hallux valgus. Excluded were studies comparing areas of surgery not specific to the control of the deformity such as use of anaesthetics or tourniquet placement. DATA COLLECTION AND ANALYSIS: Methodological quality of trials which met the inclusion criteria was independently assessed by two reviewers. Data extraction was undertaken by two reviewers. The trials were grouped according to the interventions being compared, but the dissimilarity in the comparisons prevented pooling of results. MAIN RESULTS: The methodological quality of the 21 included trials was generally poor and trial sizes were small. Three trials involving 332 participants evaluated conservative treatments versus no treatment. There was no evidence of a difference in outcomes between treatment and no treatment. One good quality trial involving 140 participants compared surgery to conservative treatment. Evidence was shown of an improvement in all outcomes in patients receiving chevron osteotomy compared with those receiving orthoses. The same trial also compared surgery to no treatment in 140 participants. Evidence was shown of an improvement in all outcomes in patients receiving chevron osteotomy compared with those receiving no treatment. Two trials involving 133 people with hallux valgus compared Keller's arthroplasty with other surgical techniques. In general, there was no advantage or disadvantage using Keller's over the other techniques. When the distal osteotomy was compared to Keller's arthroplasty, the osteotomy showed evidence of improving the intermetatarsal angle and preserving joint range of motion. The arthroplasty was found to have less of an impact on walking ability compared to the arthrodesis. Six trials involving 309 participants compared chevron (and chevron-type) osteotomy with other techniques. The chevron osteotomy offered no advantages in these trials. For some outcomes, other techniques gave better results. Two of these trials (94 participants) compared a type of proximal osteotomy to a proximal chevron osteotomy and found no evidence of a difference in outcomes between techniques. Three trials involving 157 participants compared outcomes between original operations and surgeon's adaptations. There was no advantage found for any of the adaptations. Three trials involving 71 people with hallux valgus compared new methods of fixation to traditional methods. There was no evidence that the new methods of fixation were detrimental to the outcome of the patients. Four trials involving 162 participants evaluated methods of post-operative rehabilitation. The use of continuous passive motion appeared to give an improved range of motion and earlier recovery following surgery. Early weightbearing or the use of a crepe bandage were not found to be detrimental to final outcome. REVIEWER'S CONCLUSIONS: Only a few studies had considered conservative treatments. The evidence from these suggested that orthoses and night splints did not appear to be any more beneficial in improving outcomes than no treatment. Surgery (chevron osteotomy) was shown to be beneficial compared to orthoses or no treatment, but when compared to other osteotomies, no technique was shown to be superior to any other. Only one trial had compared an osteotomy to an arthroplasty. There was limited evidence to suggest that the osteotomy gat the osteotomy gave the better outcomes. It was notable that the numbers of participants in some trials remaining dissatisfied at follow-up were consistently high (25 to 33%), even when the hallux valgus angle and pain had improved. A few of the more recent trials used assessment scores that combine several aspects of the patients outcomes. These scoring systems are useful to the clinician when comparing techniques but are of dubious relevance to the patient if they do not address their main concern and such scoring systems are frequently unvalidated. Only one study simply asked the patient if they were better than before the treatment. Final outcomes were most frequently measured at one year, with a few trials maintaining follow-up for 3 years. Such time-scales are minimal given that the patients will be on their feet for at least another 20-30 years after treatment. Future research should include patient-focused outcomes, standardised assessment criteria and longer surveillance periods, more usefully in the region of 5-10 years.

Identification of a deletion in the mismatch repair gene, MSH2, using mouse-human cell hybrids monosomal for chromosome 2.

Hereditary non-polyposis colorectal cancer is characterized by mutations in one of the DNA mismatch repair genes, primarily MLH1, MSH2, or MSH6. We report here the identification of a genomic deletion of approximately 11.4 kb encompassing the first two exons of the MSH2 gene in two generations of an Ohio family. By Southern blot analysis, using a cDNA probe spanning the first seven exons of MSH2, an alteration in each of three different enzyme digests (including a unique 13-kb band on HindIII digests) was observed, which suggested the presence of a large alteration in the 5' region of this gene. Mouse-human cell hybrids from a mutation carrier were then generated which contained a single copy each of human chromosome 2 on which the MSH2 gene resides. Southern blots on DNA from the cell hybrids demonstrated the same, unique 13-kb band from one MSH2 allele, as seen in the diploid DNA. DNA from this same monosomal cell hybrid failed to amplify in polymerase chain reactions (PCRs) using primers to exons 1 and 2, demonstrating the deletion of these sequences in one MSH2 allele, and the breakpoints involving Alu repeats were identified by PCR amplification and sequence analysis.

Designed layer assembly: a three-dimensional framework with 74% extra-framework volume by connection of infinite two-dimensional sheets.

A coordination polymer with 74% extra-framework volume is prepared by predictable linking of the honeycomb network to generate a framework-structured solid designed with two distinct connecting ligands.

Chiral direction and interconnection of helical three-connected networks in metal-organic frameworks.

The control of the interpenetration and chirality of a family of metal-organic frameworks is discussed. These systems contain two- (A) and four-fold (B) interpenetration of helical three-connected networks generated by binding the 1,3,5-benzenetricarboxylate (btc) ligand to a metal center. These frameworks have the general formula Ni(3)(btc)(2)X(m)Y(n).solvent (where X = pyridine or 4-picoline, Y = ethylene glycol, 1,2-propanediol, 1,4-butanediol, meso-2,3-butanediol, 1,2,6-hexanetriol, glycerol). The structural and chemical effects of modifying the alcohol and aromatic amine ligands bound to the metal center include controlling the thermal stability and the degree of interpenetration. Covalent linking of the four interpenetrating networks in the A family and the switching of diol binding from mono- to bidentate are demonstrated. Recognition of chiral diols by the hand of the network helices is investigated by binding an alcohol ligand with two chiral centers of opposite sense to the same helix. This reveals the subtle nature of the helix-ligand interaction.