A flexible metal-organic framework selectively sorbs para- (pX) over meta-xylene (mX) by synergic restructuring around pX coupled with generation of unused void space upon mX loading. The nature of the structural change suggests more generally that flexible structures which are initially mismatched in terms of fit and capacity to the preferred guest are strong candidates for effective molecular separations.
host-guest systems; metal-organic frameworks; structural rearrangement; xylenes
Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.
We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.
We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells.
We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)
Eye tracking in three dimensions is novel, but established descriptors derived from two-dimensional (2D) studies are not transferable. We aimed to develop metrics suitable for statistical comparison of eye-tracking data obtained from readers of three-dimensional (3D) “virtual” medical imaging, using CT colonography (CTC) as a typical example.
Ten experienced radiologists were eye tracked while observing eight 3D endoluminal CTC videos. Subsequently, we developed metrics that described their visual search patterns based on concepts derived from 2D gaze studies. Statistical methods were developed to allow analysis of the metrics.
Eye tracking was possible for all readers. Visual dwell on the moving region of interest (ROI) was defined as pursuit of the moving object across multiple frames. Using this concept of pursuit, five categories of metrics were defined that allowed characterization of reader gaze behaviour. These were time to first pursuit, identification and assessment time, pursuit duration, ROI size and pursuit frequency. Additional subcategories allowed us to further characterize visual search between readers in the test population.
We propose metrics for the characterization of visual search of 3D moving medical images. These metrics can be used to compare readers' visual search patterns and provide a reproducible framework for the analysis of gaze tracking in the 3D environment.
Advances in knowledge:
This article describes a novel set of metrics that can be used to describe gaze behaviour when eye tracking readers during interpretation of 3D medical images. These metrics build on those established for 2D eye tracking and are applicable to increasingly common 3D medical image displays.
ROCView has been developed as an image display and response capture (IDRC) solution to image display and consistent recording of reader responses in relation to the free-response receiver operating characteristic paradigm. A web-based solution to IDRC for observer response studies allows observations to be completed from any location, assuming that display performance and viewing conditions are consistent with the study being completed. The simplistic functionality of the software allows observations to be completed without supervision. ROCView can display images from multiple modalities, in a randomised order if required. Following registration, observers are prompted to begin their image evaluation. All data are recorded via mouse clicks, one to localise (mark) and one to score confidence (rate) using either an ordinal or continuous rating scale. Up to nine “mark-rating” pairs can be made per image. Unmarked images are given a default score of zero. Upon completion of the study, both true-positive and false-positive reports can be downloaded and adapted for analysis. ROCView has the potential to be a useful tool in the assessment of modality performance difference for a range of imaging methods.
Group B Streptococcus (GBS) is a common inhabitant of the bowel and vaginal flora, with known transmission routes including sexual contact and vertical transmission from mother to infant. Foodborne transmission is also possible, as GBS is a known fish and bovine pathogen. We conducted a prospective cohort study in order to identify risk factors for acquisition.
We identified risk factors for GBS acquisition among college women (n=129) and men (n=128) followed at 3-week intervals for 3 months.
A doubling in sex acts significantly increased incidence of capsular type V by 80% (95% CI: 1.19, 2.58), and other non-Ia or Ib types combined by 40% (95% CI: 1.00, 2.06; incidence of capsular type Ia (OR=1.2; 95% CI: 0.71, 1.88 p=0.57) and Ib (OR=1.5, 95% CI: 0.75, 2.86, p=0.27) were elevated although not significantly. After adjustment for sexual activity and sexual history, gender, and eating venue, fish consumption increased risk of acquiring capsular types Ia and Ib combined 7.3 fold (95% CI: 2.34, 19.50), but not other capsular types. Beef and milk were not associated with GBS incidence.
Different GBS capsular types may have different transmission routes.
Group B Streptococcus; Fish; Sexual Behavior; Epidemiology; Capsular Type; Transmission
Objective: To determine whether social deprivation is associated with neonatal unit admission.
Setting: English district general hospital.
Method: Retrospective review of neonatal unit admission records between 1990 and 2002.
Results: There was a linear increase in admission rates with increasing deprivation. The admission rate was 6.1% of live births for infants in the most affluent quartile compared with 11.1% for those in the most deprived quartile. Admission rates for all indications except jaundice and feeding problems increased with increasing deprivation.
Conclusion: Social deprivation correlates strongly with neonatal morbidity and the need for neonatal unit admission. This finding has implications for professionals in public health and primary and secondary care.
Objective: To examine social trends in the number of singleton births and birth weight in an English health district between 1990 and 2001, using an area based deprivation index.
Design: Analysis of routinely collected hospital data.
Setting: Wirral Health District in north west England.
Participants: All 48 452 live births to Wirral residents from 1990 to 2001.
Main outcome measures: Birth numbers, birth weight, and standard deviation score for birth weights for singleton births. Townsend material deprivation scores derived from postcodes.
Results: The number of singleton births fell by 28% over the 12 years. The fall in the least deprived Townsend quartile (45%) was more than triple that in the most deprived quartile (γ = 0.045; 95% confidence interval (CI) = 0.036 to 0.054; p < 0.001). Over the study period, the mean birth weight in the least deprived Townsend quartile was 141 g higher than in the most deprived quartile. There was a highly significant association between the standard deviation score for birth weight and Townsend quartile (τ-b = -0.062; 95% CI = -0.068 to -0.055; p < 0.001). Numbers of low birth weight babies in the least deprived quartile fell disproportionately compared with those from the most deprived quartile (γ = 0.17; 95% CI = 0.09 to 0.25; p < 0.001).
Conclusion: The reduction in birth rate in the Wirral was significantly less in the most deprived districts. This was accompanied by related differences in mean birth weight and the number of low birth weight babies, indicating increasing social inequality in birth trends. Previously described social inequity in birth weight and the number of low birth weight babies continues in the north west of England.
Aim: To examine the sleeping arrangements of sudden infant death syndrome (SIDS) cases on the Wirral. In particular to determine the prevalence of bed sharing with mothers who smoke, a known risk factor for SIDS.
Methods: Retrospective study of postmortem determined cases of SIDS from 1995 to 2000 on the Wirral peninsula (population 350 000, 3500 annual births). Ambulance crew reports, case notes, health visitor reports, postmortem reports, and case discussion records were studied for each case.
Results: There were 25 cases of SIDS in the postneonatal age group over the six year period. In nine cases the baby was bed sharing with the mother, of whom seven were smokers. Five of these mothers reported using alcohol or illicit drugs on the night of their infant's death. In two further cases the baby slept on a sofa with a parent.
Conclusions: Bed sharing and smoking remain important risk factors for SIDS. Mothers should be advised ante- and postnatally of this combination of risk factors. Such advice should also include a recommendation not to sleep with their baby if under the influence of alcohol or illicit drugs, and never to sleep on a sofa with their baby. All "Child Health Record" books given to parents on the Wirral now include this advice. "Reduce the Risk" advice leaflets given to parents pre- and postnatally also now carry the recommendation, and health visitors and midwives have been educated with respect to these additions.
Each of the following papers gives an account of a different UK clinical ethics committee. The committees vary in the length of time they have been established, and also in the main focus of their work. The accounts discuss the development of the committees and some of the ethical problems that have been brought to them. The issues raised will be relevant for other National Health Service (NHS) trusts in the UK that wish to set up such a committee.
Key Words: Ethics • committee • clinical • policy • ethicist
Current methods of obtaining consent for emergency neonatal research are flawed. They risk aggravating the distress of parents of preterm and other sick neonates. This distress, and the inevitable time constraints, compromise understanding and voluntariness, essential components of adequately informed consent. Current practice may be unjust in over-representing babies of more vulnerable and deprived parents. The research findings may thus not be generalisable. Informing parents antenatally about the possible need for emergency neonatal research, with presumed consent and scope for opting out, would address these problems. It would spare parents of sick neonates, already terrified by their baby's illness, further distress. Experience with opting out suggests that recruitment might increase, thus generating earlier results, without compromising parental understanding of the nature and purpose of the research.
Key Words: consent • neonate • emergency research
patient triggered, with conventional fast rate, ventilation in a
randomised controlled trial using the incidence of chronic lung disease
as the primary outcome measure.
hundred and eighty six preterm infants with birthweights from 1000 to
2000 g, and requiring ventilation for respiratory distress syndrome
within 24 hours of birth, were randomised to receive either
conventional or trigger ventilation with the SLE 2000ventilator.
were no significant differences in the incidence of chronic lung
disease (28 day and 36 week definitions), death, pneumothorax, intraventricular haemorrhage, number of ventilator days, or length of
oxygen dependency between groups.
triggered ventilation in preterm infants with respiratory distress
syndrome is feasible. No significant differences, when compared with
conventional fast rate ventilation in important medium and longer term
outcome measures, were evident.
Mice depleted of γδ T cells by monoclonal antibody treatment and infected with Plasmodium berghei ANKA did not develop cerebral malaria (CM). In striking contrast, δ0/0 mice infected with P. berghei developed CM despite their γδ T-cell deficiency. γδ T cells appear to be essential for the pathogenesis of CM in mice having experienced normal ontogeny but not in mice genetically deprived of γδ T cells from the beginning of life.
Northern hybridization analyses of the oestrogen-inducible mRNAs pLIV1 and pS2 were compared with oestrogen receptor (ER) immunocytochemistry assessments in 40 untreated primary or early recurrent breast tumours. Significant associations were observed between pLIV1/ER (P < 0.03), pS2/ER (P < 0.001) and pLIV1/pS2 (P < 0.04) status. After disease recurrence, patients were treated with assessable courses of endocrine therapies. Positive pLIV1, pS2 and ER statuses in primary disease were consequently found to be predictive of endocrine responsiveness in the secondary lesions (P < 0.03, P < 0.02, P < 0.005 respectively). However, despite these associations, a number of pLIV1- and/or pS2-positive tumours failed to respond to therapy.
How can the new deal for juniors be implemented in today's overstretched health service? How do you get clinicians and management to work together? On the Wirral falling house officer morale and recruitment stimulated a new approach, action learning, which proved to be highly successful. Action learning is not a new approach in management terms, but it is rarely used in the health service. Guided by an experienced facilitator, a group of people learn management skills by exploring and resolving practical problems relevant to them. A group of general practitioners and consultants used action learning to teach themselves more about management and at the same time to make changes which addressed many of the junior doctors' difficulties and solved the hospital recruiting problem.
The major outer membrane protein (MOMP) of Chlamydia trachomatis was expressed in Escherichia coli. To assess whether it assembled into a conformationally correct structure at the cell surface, we characterized the recombinant MOMP (rMOMP) by Western immunoblot analysis, indirect immunofluorescence, and immunoprecipitation with monoclonal antibodies (MAbs) that recognize contiguous and conformational MOMP epitopes. Western blot analysis showed that most of the rMOMP comigrated with authentic monomer MOMP, indicating that its signal peptide was recognized and cleaved by E. coli. The rMOMP could not be detected on the cell surface of viable or formalin-killed E. coli organisms by indirect immunofluorescence staining with a MAb specific for a MOMP contiguous epitope. In contrast, the same MAb readily stained rMOMP-expressing E. coli cells that had been permeabilized by methanol fixation. A MAb that recognizes a conformational MOMP epitope and reacted strongly with formalin- or methanol-fixed elementary bodies failed to stain formalin- or methanol-fixed E. coli expressing rMOMP. Moreover, this MAb did not immunoprecipitate rMOMP from expressing E. coli cells even though it precipitated the authentic protein from lysates of C. trachomatis elementary bodies. Therefore we concluded that rMOMP was not localized to the E. coli cell surface and was not recognizable by a conformation-dependent antibody. These results indicate that rMOMP expressed by E. coli is unlikely to serve as an accurate model of MOMP structure and function. They also question the utility of rMOMP as a source of immunogen for eliciting neutralizing antibodies against conformational antigenic sites of the protein.
Trachoma and sexually transmitted diseases caused by Chlamydia trachomatis are major health problems worldwide. Epitopes on the major outer membrane protein (MOMP) of C. trachomatis have been identified as important targets for the development of vaccines. In order to examine the immunogenicity of a recombinant vector expressing a chlamydial epitope, a poliovirus hybrid was constructed in which part of neutralization antigenic site I of poliovirus type 1 Mahoney (PV1-M) was replaced by a sequence from variable domain I of the MOMP of C. trachomatis serovar A. The chlamydial sequence included the neutralization epitope VAGLEK. This hybrid was viable, grew very well compared with PV1-M, and expressed both poliovirus and chlamydial antigenic determinants. When inoculated into rabbits, this hybrid was highly immunogenic, inducing a strong response against both PV1-M and C. trachomatis serovar A. Antichlamydia titers were 10- to 100-fold higher than the titers induced by equimolar amounts of either purified MOMP or a synthetic peptide expressing the VAGLEK epitope. Furthermore, rabbit antisera raised against this hybrid neutralized chlamydial infectivity both in vitro, for hamster kidney cells, and passively in vivo, for conjunctival epithelia of cynomolgus monkeys. Because poliovirus infection induces a strong mucosal immune response in primates and humans, these results indicate that poliovirus-chlamydia hybrids could become powerful tools for the study of mucosal immunity to chlamydial infection and for the development of recombinant chlamydial vaccines.
The subcellular distribution of the alpha subunit(s) of Gi has an obvious bearing on the ability of this protein to interact with receptors and targets and on its potential to serve in still unexplored capacities. In this study, we have examined the distribution of Gi alpha by means of light and electron microscopy. The cells employed were mouse 3T3 fibroblasts, normal rat kidney fibroblasts, rat C6 glioma cells, human umbilical vein endothelial cells, and human 293 kidney fibroblasts. By indirect immunofluorescence, two patterns of Gi alpha were evident. The more prominent was that associated with phase-dense, cytoplasmic structures exhibiting a tubule-like morphology. A similar distribution was noted for mitochondria, indicating attachment to a subset of microtubules. The second pattern appeared as a diffuse, particulate fluorescence associated with the plasma membrane. By immunogold labeling and electron microscopy, two populations of Gi alpha were again evident. In this instance, labeling of the plasma membrane was the more prominent. Gold particles were most often evenly distributed along the plasma membrane and were concentrated along microspikes. The second, less abundant population of Gi alpha represented the subunit (or fragments) within lysosomes. Specificity in immunolabeling was confirmed in all instances by immunotransfer blotting, the use of antibodies differing in specificities for epitopes within Gi alpha, the absence of labeling with preimmune sera, and the decrease in labeling after preincubation of antisera with appropriate peptides. These results support the proposal that several populations of Gi alpha exist: those evident within the cytoplasm by immunofluorescence, those present at the plasma membrane, and those evident within lysosomes by immunogold labeling.
An 11 year old boy presented with severe acute hereditary coproporphyria. Despite supportive measures his condition deteriorated after admission. Haem arginate, started two days after presentation, produced appreciable inhibition of porphyrin precursor overproduction and clinical improvement.
Four pregnant mink and seven pregnant ferrets, including five with previous exposure and specific antibody, were injected intravenously with 10(8)-10(10) colony-forming units of Campylobacter jejuni. All 11 pregnancies failed 1-16 days after infection, with results ranging from fetal resorption to expulsion of dead or premature living kits. In every case, uterine contents (placenta, uterine fluid and/or kits) were culture-positive for C. jejuni. Three pregnant mink and nine pregnant ferrets, including four with previous exposure and antibody, were fed 10(9)-10(11) C. jejuni. Two of the mink aborted; kits of all three were culture-positive, but those of one female survived. Seven of the nine ferrets aborted, with two having culture-positive uterine contents. None of 28 uninfected ferret control pregnancies ended in abortion. The most prominent histological feature observed was severe placentitis, which appears to be a more likely cause of Campylobacter-induced abortion than direct pathogenic effects on infected kits. These results suggest that infection of mink or ferrets with C. jejuni during pregnancy poses a serious risk of reproductive failure, even for previously exposed females.
Over a million injuries caused by slipping of footwear are believed to require treatment by doctors every year in the United Kingdom and many domestic animals are injured by slipping. Recent research has revealed that surface roughness of solings and floors is an important determinant of grip on lubricated surfaces and it is also known that soling friction is affected by hardness. The bighorn sheep (Ovis canadensis) an animal species which has adapted to a slippery environment, was studied to elucidate optimum roughness and hardness and other features which influence grip. Four adult ewes were examined in the London Zoo. The cloven hooves of this species are very mobile and the cranial tips of the hooves are the first parts to make contact with the ground. A very small contact area ensures penetration of a film of water. Mean roughness of the contact area was found to be 53 microns Rtm and the mean hardness 63 Shore A. These characteristics appear to facilitate an excellent grip on wet slippery rock but not on smooth ice. Further studies of the feet of wild species could contribute to an understanding of the factors which determine the safety of solings and floors.
The transcription of omp1, the gene encoding the major outer membrane protein, was studied for two strains of Chlamydia psittaci, guinea pig inclusion conjunctivitis (GPIC) and mouse pneumonitis (Mn). The transcriptional initiation sites for the omp1 of each strain were mapped by S1 nuclease and primer extension analyses. Three different sizes of omp1 transcripts were observed for GPIC and four were observed for Mn. The production of these transcripts appeared to be the consequence of multiple tandem promoters. The order in which the omp1 RNA transcripts appeared during the growth cycle of the C. psittaci strains was found to differ from that of C. trachomatis.
Oral or intravenous inoculation of previously unexposed juvenile and adult ferrets with Campylobacter jejuni uniformly resulted in intestinal colonization lasting 2 to 12 days. Disease varied from mild to moderate diarrhea, which resolved in 2 to 3 days. Orally infected animals developed agglutinin titers of 8 to 256 within 3 weeks, while those infected intravenously developed titers of 256 to 2,048. Ferrets which had recovered from campylobacteriosis all developed high titers of agglutinating and bacterial antibodies but were readily colonized by subsequent oral inoculation with the same strain of C. jejuni. Orally infected ferret kits 3 to 6 weeks of age exhibited the same general pattern of infection and disease as adults, but diarrhea was somewhat more severe. Kits resolved their diarrhea in 1 to 6 days and developed agglutinin titers in serum of 16 to 32 within 3 weeks. A series of five oral or rectal inoculations of kits during the 5- to 9-week age interval resulted in progressively shorter clearance times and eventual strain-specific resistance against infection, as well as disease. Gnotobiotic adults showed the same pattern of strain-specific accelerated clearance and resistance to disease. Kits born to immune dams with high levels of whey antibodies had passively acquired serum agglutinin titers of 256 to 2,048. These kits showed no resistance to colonization with the homologous strain of C. jejuni but were completely refractory to diarrhea. These observations suggest that (i) some form(s) of specific immunity, rather than factors relating solely to age or normal flora, is responsible for resistance to C. jejuni colonization and disease production and (ii) humoral immunity at a level that does not prevent colonization can protect against enteric disease caused by this organism.