Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

The geography of demography: long-term demographic studies and species distribution models reveal a species border limited by adaptation.

Potential causes of species' geographic distribution limits fall into two broad classes: (1) limited adaptation across spatially variable environments and (2) limited opportunities to colonize unoccupied areas. Combining demographic studies, analyses of demographic responses to environmental variation, and species distribution models, we investigated the causes of range limits in a model system, the eastern border of the California annual plant Clarkia xantiana ssp. xantiana. Vital rates of 20 populations varied with growing season temperature and precipitation: fruit number and overwinter survival of 1-year-old seeds declined steeply, while current-year seed germination increased modestly along west-to-east gradients in decreasing temperature, decreasing mean precipitation, and increasing variation in precipitation. Long-term stochastic finite rate of increase, λ(s), exhibited a fourfold range and varied among geologic surface materials as well as with temperature and precipitation. Growth rate declined significantly toward the eastern border, falling below 1 in three of the five easternmost populations. Distribution models employing demographically important environmental variables predicted low habitat favorability beyond the eastern border. Models that filtered or weighted population presences by λ(s) predicted steeper eastward declines in favorability and assigned greater roles in setting the distribution to among-year variation in precipitation and to geologic surface material. These analyses reveal a species border likely set by limited adaptation to declining environmental quality.

A focused ethnography of a Child and Adolescent Mental Health Service: factors relevant to the implementation of a depression trial.

BACKGROUND: Prior to commencing a randomised controlled trial, we conducted a focused ethnography to ensure that the trial was well suited to the proposed setting. METHODS: A six-month observation of a Child and Adolescent Mental Health Service site in the North-East of England was undertaken to observe the site procedures, staff culture and patient care pathways. During this period, documentary data were collected and interviews were conducted with key informants to provide insight into staff perceptions of the proposed trial. The data were coded using thematic analysis and the resulting themes were verified by a second coder. RESULTS: Seventeen documents were collected, 158 h of observation and six formal staff interviews were undertaken. Four themes emerged from the data; non-clinically orientated variation in practice, diagnosis, capacity and staff economy. Non-clinically orientated variation in practice occurred when staff decisions were based upon resource availability rather than on clinical judgement. Diagnosis demonstrated differing staff confidence in making diagnoses and in the treatment of patients who had received a diagnosis. Capacity consisted of the time to attend training and the psychological capacity to consider or incorporate learning into practice. Staff economy was characterised by staff changes and shortages. There was significant interaction between the themes, with staff economy emerging as a central barrier to research. The results directly informed adaptations to the trial protocol. CONCLUSIONS: An ethnographic approach has provided important insights into the individual, practical and organisational boundaries into which a trial would need to be implemented.

Sequence diversity in the tetraploid Zea perennis and the closely related diploid Z. diploperennis: insights from four nuclear loci.

Polyploidy has been an extremely common phenomenon in the evolutionary history of angiosperms. Despite this there are few data available to evaluate the effects of polyploidy on genetic diversity and to compare the relative effects of drift and selection in polyploids and related diploids. We investigated DNA sequence diversity at four nuclear loci (adh1, glb1, c1, and waxy) from the tetraploid Zea perennis and the closely related diploid Z. diploperennis. Contrary to expectations, we detected no strong evidence for greater genetic diversity in the tetraploid, or for consistent differences in the effects of either drift or selection between the tetraploid and the diploid. Our failure to find greater genetic diversity in Z. perennis may result from its relatively recent origin or demographic factors associated with its origin. In addition to comparing genetic diversity in the two species, we constructed genealogies to infer the evolutionary origin of Z. perennis. Although these genealogies are equivocal regarding the mode of origin, several aspects of these genealogies support an autotetraploid origin. Consistent with previous molecular data the genealogies do not, however, support the division of Zea into two sections, the section Zea and the section Luxuriantes.

Measuring tolerance to herbivory: accuracy and precision of estimates made using natural versus imposed damage.

Tolerance to herbivory (the ability of a plant to incur herbivore damage without a corresponding reduction in fitness) can be measured using either naturally occurring or imposed herbivore damage. After briefly reviewing some of the advantages and disadvantages of these approaches, we present calculations describing the degree to which estimates of tolerance will be biased by environmental variables that affect both herbivory and fitness. With naturally occurring herbivory the presence of environmental variables that are correlated with herbivory and fitness will result in biased estimates of tolerance. In contrast, estimates obtained from experiments in which herbivory is artificially imposed will be unbiased; however, under a wide range of parameter values these estimates will be less precise than estimates obtained from experiments in which herbivory is not manipulated.

Asymmetrical crossing barriers in angiosperms.

Patterns of reproductive isolation between species may provide insight into the mechanisms and evolution of barriers to interspecific gene exchange. We used data from published interspecific hybridization experiments from 14 genera of angiosperms in order to test for the presence of asymmetrical barriers to gene exchange. Reproductive isolation was examined at three life-history stages: the ability of interspecific crosses to produce seeds, the viability of F1 hybrids, and the fertility of F1 hybrids. Statistically significant asymmetries in the strength of reproductive isolation between species were detected in all genera and at each of the three life-history stages. Asymmetries in seed production may be caused by a variety of mechanisms including differences in stigma/style lengths, self compatibility and differential fruit abortion. Asymmetries in post-zygotic isolation are probably caused by nuclear-cytoplasmic interactions. Asymmetrical reproductive isolation between plant taxa may have important implications for the dynamics of hybrid zones, the direction of genetic introgression and the probability of reinforcement.

Pharmacokinetic and pharmacodynamic responses to caffeine in poor and normal sleepers.

Pharmacokinetic and pharmacodynamic responses to caffeine (2.5 mg/kg) were compared between ten healthy self-rated poor sleepers and ten normal sleepers. Sleep pattern assessed by the Pittsburgh Sleep Quality Index (PSQI). There was no significant difference in mean estimated daily caffeine consumption between the groups. The poor sleepers had significantly higher scores for neuroticism on the Eysenck Personality Questionnaire (EPQ) and anxiety on the Hospital Anxiety Depression (HAD) scale, compared with normal sleepers. Caffeine pharmacokinetics were assessed by measurement of saliva caffeine concentrations. Poor sleepers showed significantly greater variability in caffeine Cmax, clearance had half-life, compared to normal sleepers. Pharmacodynamic measures included heart rate, blood pressure, visual analogue scales for concentration, vigilance and relaxation, psychomotor performance [Digit Symbol Substitution Test (DSST) and tapping rate (TR)] and EEG activity [Contingent negative variation (CNV), auditory evoked potential and power spectral analysis]. Prior to caffeine administration, poor sleepers compared to normal sleepers had faster heart rates, lower ratings for concentration and relaxation, poorer performance on the DSST, greater CNV magnitude, faster peak alpha frequency and lower delta, theta and beta power. These differences persisted after caffeine ingestion and overall differences between the groups on these measures were significant (P < 0.01-.001). Post-dose, but not pre-dose, scores for vigilance and TR were significantly lower overall in poor compared with normal sleepers. Despite the baseline differences between poor and normal sleepers, the changes following caffeine administration were similar in direction and magnitude in both groups.

The use of antiepileptic drugs in learning disabled people with epilepsy: an audit of adult in-patients in a treatment and continuing care service.

The primary aim of the audit described was to examine antiepileptic drug use among adult in-patients with learning disability. A secondary aim was to examine investigation in those patients. For the purposes of this paper "Learning disability" is synonymous with ICD-10 "Mental Retardation", "Mental Handicap" or "Intellectual Impairment" and should not be confused with the North American use of the term which refers to discrete, specific problems in mental abilities such as reading. A total of 75 adult patients on both the Northgate and Prudhoe sites (managed by Northgate and Prudhoe NHS Trust) were identified as being treated with antiepileptic drugs (AEDs) for postulated epilepsy. Only 12 (16%) patients were being treated with three AEDs or more, the remainder being on either one or two AEDs. All patients with a history of status epilepticus were prescribed rectal diazepam or, more rarely, intranasal midazolam. The number and type of investigations performed on patients varied widely and was sometimes limited by the patient's ability to co-operate with procedures. Overall, 28 patients were identified who might benefit from a reduction in the number of AEDs prescribed. In 15 of these patients antiepileptic drug regime was currently being reduced. The increased utilization of sleep/sedated electroencephalogram (EEG) and magnetic resonance imaging (MRI--for partial seizures), where practical, may also increase diagnostic accuracy in identifying epilepsy and its aetiology. Audit will be repeated in 12 months.

Presenting features and early management of childhood intermittent exotropia in the UK: inception cohort study.

AIM: To investigate factors associated with early management of intermittent exotropia (X(T)) in hospital eye departments in the UK in a prospective cohort study. METHODS: An inception cohort of 460 children aged <12 years with previously untreated X(T) (mean age 3.6 years, 55.9% girls) was recruited from 26 UK hospital children's eye clinics and orthoptic departments. Participants received a standard ophthalmic examination at recruitment and orthoptic assessment at three-monthly intervals thereafter. The influence of severity of exotropia (control measured by Newcastle Control Score (NCS), and angle of strabismus, visual acuity and stereoacuity) and age on the type of management was investigated. RESULTS: Within the first 12 months following recruitment, 297 (64.6%) children received no treatment, either for impaired visual acuity or for strabismus. Ninety-six (21%) children had treatment for impaired visual acuity. Eighty-nine (19.4%) received treatment for strabismus (22 of whom also received treatment for defective visual acuity); in 54 (11.7%) treatment was non-surgical and in 35 (7.6%) eye muscle surgery was performed. Children with poor (score 7-9) control of strabismus at recruitment were more likely to have surgery than children with good (score 1-3) control (p<0.001). Children who had no treatment were younger (mean age 3.38 years) than those who were treated (mean 4.07 years) (p<0.001). Stereoacuity and size of the angle of strabismus did not influence the type of management received. CONCLUSIONS: X(T) can be a presenting sign of reduced visual acuity. Most children with well controlled X(T) receive no treatment within 12 months following presentation.

Molecular evolution of the wound-induced serine protease inhibitor wip1 in Zea and related genera.

Plant defense mechanisms have been the subject of intensive investigation. However, little is known about their long-term evolutionary dynamics. We investigated the molecular diversity of a wound-induced serine protease inhibitor, wip1, in the genus Zea, as well as the divergence of wip1 among four genera, Zea, Tripsacum, Sorghum, and Oryza, in order to gain insight into the long-term evolution of plant defense. The specific objectives of this study were to determine (1) whether wip1 has a history of positive or balancing selection, as has been shown for genes involved in plant defense against pathogens, and (2) if the evolutionary histories of wip1 inhibitory loops, which come into closest contact with proteases, differ from the evolutionary history of other parts of this gene. The Zea polymorphism data are consistent with a neutral evolutionary history. In contrast, relative-rate tests suggest a nonneutral evolutionary history. This inconsistency may indicate that selection acting on wip1 is episodic or that wip1 evolves in response to selection favoring novel alleles. We also detected significant heterogeneity in the evolutionary rates of the two inhibitory loops of wip1-one inhibitory loop is highly conserved, whereas the second has diverged rapidly. Because these two inhibitory loops are predicted to have very similar biochemical functions, the significantly different evolutionary histories suggest that these loops have different ecological functions.

Patterns of evolutionary rate variation among genes of the anthocyanin biosynthetic pathway.

The anthocyanin biosynthetic pathway is responsible for the production of anthocyanin pigments in plant tissues and shares a number of enzymes with other biochemical pathways. The six core structural genes of this pathway have been cloned and characterized in two taxonomically diverse plant species (maize and snapdragon). We have recently cloned these genes for a third species, the common morning glory, Ipomoea purpurea. This additional information provides an opportunity to examine patterns of evolution among genes within a single biochemical pathway. We report here that upstream genes in the anthocyanin pathway have evolved substantially more slowly than downstream genes and suggest that this difference in evolutionary rates may be explained by upstream genes being more constrained because they participate in several different biochemical pathways. In addition, regulatory genes associated with the anthocyanin pathway tend to evolve more rapidly than the structural genes they regulate, suggesting that adaptive evolution of flower color may be mediated more by regulatory than by structural genes. Finally, for individual anthocyanin genes, we found an absence of rate heterogeneity among three major angiosperm lineages. This rate constancy contrasts with an accelerated rate of evolution of three CHS-like genes in the Ipomoea lineage, indicating that these three genes have diverged without coordinated adjustment by other pathway genes.

Acute acquired comitant esotropia: a prospective study.

PURPOSE: To define the clinical characteristics of patients presenting with acute onset esotropia and features suggestive of possible underlying central nervous system pathology. To assess the prognosis for the return of binocular function and to consider the most appropriate management. METHODS: A prospective clinical study was carried out of all patients presenting to the department of paediatric ophthalmology at a university teaching hospital over the period January 1994 to April 1997. Each patient underwent a full ophthalmological examination (including assessment of sensory status). All patients were referred to a paediatric neurologist for examination and CT and/or MRI scan. RESULTS: Ten patients presented during the study period. Uncorrected hypermetropia and/or decompensated monofixation syndrome were the commonest aetiological factors. One patient was found to have a cerebellar tumour. In 5 patients prescription of the full hypermetropic correction alone was sufficient to restore binocularity. Five patients required bilateral medial rectus recession. Binocular function was restored in all cases--in 5 cases with bifoveal fusion. CONCLUSION: Decompensation of a pre-existing phoria or monofixation syndrome appears the commonest aetiology. Prescription of the full hypermetropic correction found at cycloplegic refraction forms an essential part of initial management. No single clinical sign can reliably indicate the rare patient harbouring a tumour. A high index of suspicion should be maintained and neuro-imaging considered in the absence of expected findings such as hypermetropia or fusion potential or in the presence of atypical features or neurological signs.

Acquired palsy of the oculomotor, trochlear and abducens nerves.

There have been few studies primarily concerned with the relative frequencies, aetiologies and prognoses of ocular motor palsies. Those published have emanated largely from neurological tertiary referral centres rather than primary ophthalmology departments. We have performed a retrospective study of all patients with acquired III, IV or VI cranial nerve palsy who were seen in the orthoptic department at Ninewells Hospital, Dundee, over the 9 year period from 1984 to 1992. A total of 165 cases were identified. VI nerve palsies accounted for the majority of patients (57%), with IV nerve palsies (21%) occurring more frequently than III nerve palsies (17%) and multiple palsies (5%). Thirty-five per cent of cases were of unknown aetiology and 32% of vascular aetiology. The incidence of sinister pathology-neoplasia (2%) and aneurysm (1%)-was surprisingly low. Fifty-seven per cent of all patients made a total recovery (in a median time of 3 months) and 80% made at least a partial recovery. The results are contrasted with those of previous studies and the value of associated symptoms and of further investigation in the assessment of these patients is discussed.

Clinical features of progressive bifocal chorioretinal atrophy: a retinal dystrophy linked to chromosome 6q.

PURPOSE: The gene for progressive bifocal chorioretinal atrophy (PBCRA) has been linked to chromosome 6q, near the genomic assignment for North Carolina macular dystrophy. A study was undertaken to define the clinical features of a large PBCRA pedigree and to determine whether PBCRA and North Carolina macular dystrophy are phenotypically distinct entities. METHODS: Fifteen affected individuals from 1 large family were examined clinically, which included angiography and electrophysiologic studies. RESULTS: The PBCRA is an autosomal dominant chorioretinal dystrophy of early onset characterized by large atrophic macular and nasal retinal lesions, nystagmus, myopia, poor vision, and slow progression. A large atrophic macular lesion and nasal subretinal deposits are evident soon after birth. An atrophic area nasal to the optic nerve head appears in the second decade, which enlarges progressively. Electro-oculographic and electroretinographic studies indicated marked, diffuse abnormalities of rod and cone function. Fluorescein and indocyanine green angiography showed a large circumscribed area of macular choroidal atrophy with staining of deposits in the peripheral retina. In addition to previously documented features, nasal retinal abnormalities from a few weeks of age, marked photopsia in a number of patients, and retinal detachments in three eyes are reported as new features of the disease. CONCLUSIONS: An extended description of PBCRA is presented highlighting that the phenotype is distinct from North Carolina macular dystrophy, although some phenotypic similarities exist between the two conditions. These disorders may be the result of different mutations on the same gene or nearby genes.

Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q.

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare, autosomal dominant congenital chorioretinal dystrophy. We have performed genetic linkage analysis on a five-generation British pedigree. Two-point linkage analysis showed significant linkage with nine microsatellite marker loci mapping to chromosome 6q. Multipoint analysis gave a maximum lod score of 11.8 (theta = 0.05) between D6S249 and D6S283. This region overlaps with that to which the gene for North Carolina macular dystrophy (MCDR1) has been assigned. However, given the range of differences in phenotype between these two retinal disorders, it is likely that different mutation mechanisms are responsible for each disease.