BACKGROUND

Plants are often subjected to periods of soil and atmospheric water deficits during their life cycle as well as, in many areas of the globe, to high soil salinity. Understanding how plants respond to drought, salt and co-occurring stresses can play a major role in stabilizing crop performance under drought and saline conditions and in the protection of natural vegetation. Photosynthesis, together with cell growth, is among the primary processes to be affected by water or salt stress.

METHODS

The effects of drought and salt stresses on photosynthesis are either direct (as the diffusion limitations through the stomata and the mesophyll and the alterations in photosynthetic metabolism) or secondary, such as the oxidative stress arising from the superimposition of multiple stresses. The carbon balance of a plant during a period of salt/water stress and recovery may depend as much on the velocity and degree of photosynthetic recovery, as it depends on the degree and velocity of photosynthesis decline during water depletion. Current knowledge about physiological limitations to photosynthetic recovery after different intensities of water and salt stress is still scarce. From the large amount of data available on transcript-profiling studies in plants subjected to drought and salt it is becoming apparent that plants perceive and respond to these stresses by quickly altering gene expression in parallel with physiological and biochemical alterations; this occurs even under mild to moderate stress conditions. From a recent comprehensive study that compared salt and drought stress it is apparent that both stresses led to down-regulation of some photosynthetic genes, with most of the changes being small (ratio threshold lower than 1) possibly reflecting the mild stress imposed. When compared with drought, salt stress affected more genes and more intensely, possibly reflecting the combined effects of dehydration and osmotic stress in salt-stressed plants.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

We have hypothesized that end-to-end chromosome fusions observed in some tumours could play a part in genetic instability associated with tumorigenesis and that fusion may result from the loss of the long stretches of G-rich repeats found at the ends of all linear chromosomes. We therefore asked whether there is telomere loss or reduction in common tumours. Here we show that in most of the colorectal carcinomas that we analysed, there is a reduction in the length of telomere repeat arrays relative to the normal colonic mucosa from the same patient. We speculate on the consequences of this loss for tumorigenesis. We also show that the telomere arrays are much smaller in colonic mucosa and blood than in fetal tissue and sperm, and that there is a reduction in average telomere length with age in blood and colon mucosa. We propose that the telomerase is inactive in somatic tissues, and that telomere length is an indicator of the number of cell divisions that it has taken to form a particular tissue and possibly to generate tumours.

In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.

Controversy still exists on the optimal surgical resection for potentially curable gastric cancer. Much better long-term survival has been reported in retrospective/non-randomized studies with D2 resections that involve a radical extended regional lymphadenectomy than with the standard D1 resections. In this paper we report the long-term survival of patients entered into a randomized study, with follow-up to death or 3 years in 96% of patients and a median follow-up of 6.5 years. In this prospective trial D1 resection (removal of regional perigastric nodes) was compared with D2 resection (extended lymphadenectomy to include level 1 and 2 regional nodes). Central randomization followed a staging laparotomy. Out of 737 patients with histologically proven gastric adenocarcinoma registered, 337 patients were ineligible by staging laparotomy because of advanced disease and 400 were randomized. The 5-year survival rates were 35% for D1 resection and 33% for D2 resection (difference -2%, 95% CI = -12%-8%). There was no difference in the overall 5-year survival between the two arms (HR = 1.10, 95% CI 0.87-1.39, where HR>> 1 implies a survival benefit to D1 surgery). Survival based on death from gastric cancer as the event was similar in the D1 and D2 groups (HR = 1.05, 95% CI 0.79-1.39) as was recurrence-free survival (HR = 1.03, 95% CI 0.82-1.29). In a multivariate analysis, clinical stages II and III, old age, male sex and removal of spleen and pancreas were independently associated with poor survival. These findings indicate that the classical Japanese D2 resection offers no survival advantage over D1 surgery. However, the possibility that D2 resection without pancreatico-splenectomy may be better than standard D1 resection cannot be dismissed by the results of this trial.

We present a refined model of the alpha beta-tubulin dimer to 3.5 A resolution. An improved experimental density for the zinc-induced tubulin sheets was obtained by adding 114 electron diffraction patterns at 40-60 degrees tilt and increasing the completeness of structure factor amplitudes to 84.7 %. The refined structure was obtained using maximum-likelihood including phase information from experimental images, and simulated annealing Cartesian refinement to an R-factor of 23.2 and free R-factor of 29.7. The current model includes residues alpha:2-34, alpha:61-439, beta:2-437, one molecule of GTP, one of GDP, and one of taxol, as well as one magnesium ion at the non-exchangeable nucleotide site, and one putative zinc ion near the M-loop in the alpha-tubulin subunit. The acidic C-terminal tails could not be traced accurately, neither could the N-terminal loop including residues 35-60 in the alpha-subunit. There are no major changes in the overall fold of tubulin with respect to the previous structure, testifying to the quality of the initial experimental phases. The overall geometry of the model is, however, greatly improved, and the position of side-chains, especially those of exposed polar/charged groups, is much better defined. Three short protein sequence frame shifts were detected with respect to the non-refined structure. In light of the new model we discuss details of the tubulin structure such as nucleotide and taxol binding sites, lateral contacts in zinc-sheets, and the significance of the location of highly conserved residues.

The precise excision of introns from pre-messenger RNA is performed by the spliceosome, a macromolecular machine containing five small nuclear RNAs and numerous proteins. Much has been learned about the protein components of the spliceosome from analysis of individual purified small nuclear ribonucleoproteins and salt-stable spliceosome 'core' particles. However, the complete set of proteins that constitutes intact functional spliceosomes has yet to be identified. Here we use maltose-binding protein affinity chromatography to isolate spliceosomes in highly purified and functional form. Using nanoscale microcapillary liquid chromatography tandem mass spectrometry, we identify approximately 145 distinct spliceosomal proteins, making the spliceosome the most complex cellular machine so far characterized. Our spliceosomes comprise all previously known splicing factors and 58 newly identified components. The spliceosome contains at least 30 proteins with known or putative roles in gene expression steps other than splicing. This complexity may be required not only for splicing multi-intronic metazoan pre-messenger RNAs, but also for mediating the extensive coupling between splicing and other steps in gene expression.

BACKGROUND

This study examined the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood.

METHODS

We analyzed data from published follow-up studies of ADHD. To be included in the analysis, these additional studies had to meet the following criteria: the study included a control group and it was clear from the methods if the diagnosis of ADHD included subjects who did not meet full criteria but showed residual and impairing signs of the disorder. We used a meta-analysis regression model to separately assess the syndromatic and symptomatic persistence of ADHD.

RESULTS

When we define only those meeting full criteria for ADHD as having 'persistent ADHD', the rate of persistence is low, approximately 15% at age 25 years. But when we include cases consistent with DSM-IV's definition of ADHD in partial remission, the rate of persistence is much higher, approximately 65%.

CONCLUSIONS

Our results show that estimates of ADHD's persistence rely heavily on how one defines persistence. Yet, regardless of definition, our analyses show that evidence for ADHD lessens with age. More work is needed to determine if this reflects true remission of ADHD symptoms or is due to the developmental insensitivity of diagnostic criteria for the disorder.

Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.

In the early 1970s, Andersen and colleagues proposed that the principal excitatory pathways of the hippocampal formation were organized in a lamellar fashion. This proposition, based heavily on the physiological studies of the proponents, indicated that "a point source of entorhinal activity projects its impulses through the four membered pathway (of the hippocampal formation) along a slice or lamella, of hippocampal tissue oriented normally to the alvear surface" [Anderson P., Bliss V.P. and Skrede K. K. (1971) Expl Brain Res. 13, 222-238] and perpendicular to the long axis of the hippocampus. Andersen et al. further suggested that, "By means of this lamellar organization, small strips of the hippocampal cortex may operate as independent functional units, although excitatory and inhibitory transverse connections may modify the behavior of neighboring lamellae." The "lamellar hypothesis" of hippocampal anatomical organization has had tremendous influence on the conceptualization of hippocampal information processing and was largely responsible for prompting the establishment of the in vitro hippocampal slice technology. While the "lamellar hypothesis" was consistent with the known neuroanatomy, subsequent neuroanatomical investigations, using a variety of modern tracing techniques, have invariably demonstrated that all of the major hippocampal projections, except for those arising from the granule cells of the dentate gyrus, are much more divergent than would be consistent with a strict interpretation of the lamellar hypothesis. This has become particularly clear in ongoing studies of the intrinsic hippocampal projections using the recently introduced anterograde tracer, Phaseolus vulgaris leucoagglutinin. Citing the conclusions from several papers dealing with the anatomical organization of the hippocampal formation and using examples from recent Phaseolus vulgaris leucoagglutinin mapping studies, the following are demonstrated. (1) That the major hippocampal projections are as extensive and highly organized in the long or septotemporal axis of the hippocampus as in the transverse axis. (2) That at least some of the hippocampal projections, such as the associational projections arising from the dentate gyrus, appear to be specifically organized to integrate distant levels of the hippocampal formation. (3) That the physiological data of Anderson et al. can be re-interpreted in the light of these new anatomical data to show how the stimulation and recording protocols used at the time would, in fact, generate the appearance of a lamellar organization. It is concluded that it is heuristically most reasonable to consider the hippocampal formation as a three-dimensional cortical region with important information processing taking place in both the transverse and long axes.(ABSTRACT TRUNCATED AT 400 WORDS)

Codon usage data has been compiled for 110 yeast genes. Cluster analysis on relative synonymous codon usage revealed two distinct groups of genes. One group corresponds to highly expressed genes, and has much more extreme synonymous codon preference. The pattern of codon usage observed is consistent with that expected if a need to match abundant tRNAs, and intermediacy of tRNA-mRNA interaction energies are important selective constraints. Thus codon usage in the highly expressed group shows a higher correlation with tRNA abundance, a greater degree of third base pyrimidine bias, and a lesser tendency to the A+T richness which is characteristic of the yeast genome. The cluster analysis can be used to predict the likely level of gene expression of any gene, and identifies the pattern of codon usage likely to yield optimal gene expression in yeast.

As the sole site of nucleocytoplasmic transport, the nuclear pore complex (NPC) has a vital cellular role. Nonetheless, much remains to be learned about many fundamental aspects of NPC function. To further understand the structure and function of the mammalian NPC, we have completed a proteomic analysis to identify and classify all of its protein components. We used mass spectrometry to identify all proteins present in a biochemically purified NPC fraction. Based on previous characterization, sequence homology, and subcellular localization, 29 of these proteins were classified as nucleoporins, and a further 18 were classified as NPC-associated proteins. Among the 29 nucleoporins were six previously undiscovered nucleoporins and a novel family of WD repeat nucleoporins. One of these WD repeat nucleoporins is ALADIN, the gene mutated in triple-A (or Allgrove) syndrome. Our analysis defines the proteome of the mammalian NPC for the first time and paves the way for a more detailed characterization of NPC structure and function.

We describe a DNA sequencing technology in which a commonly available, inexpensive epifluorescence microscope is converted to rapid nonelectrophoretic DNA sequencing automation. We apply this technology to resequence an evolved strain of Escherichia coli at less than one error per million consensus bases. A cell-free, mate-paired library provided single DNA molecules that were amplified in parallel to 1-micrometer beads by emulsion polymerase chain reaction. Millions of beads were immobilized in a polyacrylamide gel and subjected to automated cycles of sequencing by ligation and four-color imaging. Cost per base was roughly one-ninth as much as that of conventional sequencing. Our protocols were implemented with off-the-shelf instrumentation and reagents.

BACKGROUND

The aim of the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase as thrombolytic therapy within the first 3 h of onset of acute ischaemic stroke. Under European Union regulations, SITS-MOST was required to assess the safety profile of alteplase in clinical practice by comparison with results in randomised controlled trials.

METHODS

6483 patients were recruited from 285 centres (50% with little previous experience in stroke thrombolysis) in 14 countries between 2002 and 2006 for this prospective, open, monitored, observational study. Primary outcomes were symptomatic (a deterioration in National Institutes of Health stroke scale score of>>or=4) intracerebral haemorrhage type 2 within 24 h and mortality at 3 months. We compared mortality, the proportion of patients with symptomatic intracerebral haemorrhage as per the Cochrane definition, and functional outcome at 3 months with relevant pooled results from randomised controlled trials.

RESULTS

Baseline characteristics of patients in SITS-MOST were much the same as those in the pooled randomised controlled trials. At 24 h, the proportion of patients with symptomatic intracerebral haemorrhage (per the SITS-MOST protocol) was 1.7% (107/6444; 95% CI 1.4-2.0); at 7 days, the proportion with the same condition as per the Cochrane definition was 7.3% (468/6438; 6.7-7.9) compared with 8.6% (40/465; 6.3-11.6) in the pooled randomised controlled trials. The mortality rate at 3 months in SITS-MOST was 11.3% (701/6218; 10.5-12.1) compared with 17.3% (83/479; 14.1-21.1) in the pooled randomised controlled trials.

CONCLUSIONS

These data confirm that intravenous alteplase is safe and effective in routine clinical use when used within 3 h of stroke onset, even by centres with little previous experience of thrombolytic therapy for acute stroke. The findings should encourage wider use of thrombolytic therapy for suitable patients treated in stroke centres.

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.

In 1903, Leishman and Donovan separately described the protozoan now called Leishmania donovani in splenic tissue from patients in India with the life-threatening disease now called visceral leishmaniasis. Almost a century later, many features of leishmaniasis and its major syndromes (ie, visceral, cutaneous, and mucosal) have remained the same; but also much has changed. As before, epidemics of this sandfly-borne disease occur periodically in India and elsewhere; but leishmaniasis has also emerged in new regions and settings, for example, as an AIDS-associated opportunistic infection. Diagnosis still typically relies on classic microbiological methods, but molecular-based approaches are being tested. Pentavalent antimony compounds have been the mainstay of antileishmanial therapy for half a century, but lipid formulations of amphotericin B (though expensive and administered parenterally) represent a major advance for treating visceral leishmaniasis. A pressing need is for the technological advances in the understanding of the immune response to leishmania and the pathogenesis of leishmaniasis to be translated into field-applicable and affordable methods for diagnosis, treatment, and prevention of this disease.

Rates of molecular evolution vary widely between lineages, but quantification of how rates change has proven difficult. Recently proposed estimation procedures have mainly adopted highly parametric approaches that model rate evolution explicitly. In this study, a semiparametric smoothing method is developed using penalized likelihood. A saturated model in which every lineage has a separate rate is combined with a roughness penalty that discourages rates from varying too much across a phylogeny. A data-driven cross-validation criterion is then used to determine an optimal level of smoothing. This criterion is based on an estimate of the average prediction error associated with pruning lineages from the tree. The methods are applied to three data sets of six genes across a sample of land plants. Optimally smoothed estimates of absolute rates entailed 2- to 10-fold variation across lineages.

Mitochondrial DNA (mtDNA) has been used to study molecular ecology and phylogeography for 25 years. Much important information has been gained in this way, but it is time to reflect on the biology of the mitochondrion itself and consider opportunities for evolutionary studies of the organelle itself and its ecology, biochemistry and physiology. This review has four sections. First, we review aspects of the natural history of mitochondria and their DNA to show that it is a unique molecule with specific characteristics that differ from nuclear DNA. We do not attempt to cover the plethora of differences between mitochondrial and nuclear DNA; rather we spotlight differences that can cause significant bias when inferring demographic properties of populations and/or the evolutionary history of species. We focus on recombination, effective population size and mutation rate. Second, we explore some of the difficulties in interpreting phylogeographical data from mtDNA data alone and suggest a broader use of multiple nuclear markers. We argue that mtDNA is not a sufficient marker for phylogeographical studies if the focus of the investigation is the species and not the organelle. We focus on the potential bias caused by introgression. Third, we show that it is not safe to assume a priori that mtDNA evolves as a strictly neutral marker because both direct and indirect selection influence mitochondria. We outline some of the statistical tests of neutrality that can, and should, be applied to mtDNA sequence data prior to making any global statements concerning the history of the organism. We conclude with a critical examination of the neglected biology of mitochondria and point out several surprising gaps in the state of our knowledge about this important organelle. Here we limelight mitochondrial ecology, sexually antagonistic selection, life-history evolution including ageing and disease, and the evolution of mitochondrial inheritance.

In recent years, deep artificial neural networks (including recurrent ones) have won numerous contests in pattern recognition and machine learning. This historical survey compactly summarizes relevant work, much of it from the previous millennium. Shallow and Deep Learners are distinguished by the depth of their credit assignment paths, which are chains of possibly learnable, causal links between actions and effects. I review deep supervised learning (also recapitulating the history of backpropagation), unsupervised learning, reinforcement learning & evolutionary computation, and indirect search for short programs encoding deep and large networks.

Humans continue to transform the global nitrogen cycle at a record pace, reflecting an increased combustion of fossil fuels, growing demand for nitrogen in agriculture and industry, and pervasive inefficiencies in its use. Much anthropogenic nitrogen is lost to air, water, and land to cause a cascade of environmental and human health problems. Simultaneously, food production in some parts of the world is nitrogen-deficient, highlighting inequities in the distribution of nitrogen-containing fertilizers. Optimizing the need for a key human resource while minimizing its negative consequences requires an integrated interdisciplinary approach and the development of strategies to decrease nitrogen-containing waste.

Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain, such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed, without radiographs, for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees, pain present on internal rotation of the hip, morning stiffness of the hip for less than or equal to 60 minutes, and age greater than 50 years, or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained, hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular), joint space narrowing (superior, axial, and/or medial), and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set, the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.

BACKGROUND

The SF-6D and EQ-5D are both preference-based measures of health. Empirical work is required to determine what the smallest change is in utility scores that can be regarded as important and whether this change in utility value is constant across measures and conditions.

OBJECTIVE

To use distribution and anchor-based methods to determine and compare the minimally important difference (MID) for the SF-6D and EQ-5D for various datasets.

METHODS

The SF-6D is scored on a 0.29-1.00 scale and the EQ-5D on a -0.59-1.00 scale, with a score of 1.00 on both, indicating 'full health'. Patients were followed for a period of time, then asked, using question 2 of the SF-36 as our anchor, if their general health is much better (5), somewhat better (4), stayed the same (3), somewhat worse (2) or much worse (1) compared to the last time they were assessed. We considered patients whose global rating score was 4 or 2 as having experienced some change equivalent to the MID. This paper describes and compares the MID and standardised response mean (SRM) for the SF-6D and EQ-5D from eight longitudinal studies in 11 patient groups that used both instruments.

RESULTS

From the 11 reviewed studies, the MID for the SF-6D ranged from 0.011 to 0.097, mean 0.041. The corresponding SRMs ranged from 0.12 to 0.87, mean 0.39 and were mainly in the 'small to moderate' range using Cohen's criteria, supporting the MID results. The mean MID for the EQ-5D was 0.074 (range -0.011-0.140) and the SRMs ranged from -0.05 to 0.43, mean 0.24. The mean MID for the EQ-SD was almost double that of the mean MID for the SF-6D.

CONCLUSIONS

There is evidence that the MID for these two utility measures are not equal and differ in absolute values. The EQ-5D scale has approximately twice the range of the SF-6D scale. Therefore, the estimates of the MID for each scale appear to be proportionally equivalent in the context of the range of utility scores for each scale. Further empirical work is required to see whether or not this holds true for other utility measures, patient groups and populations.

We assume that each class of protein has a core structure that is defined by internal residues, and that the external, solvent-contacting residues contribute to the stability of the structure, are of primary importance to function, but do not determine the architecture of the core portions of the polypeptide chain. An algorithm has been developed to supply a list of permitted sequences of internal residues compatible with a known core structure. This list is referred to as the tertiary template for that structure. In general the positions in the template are not sequentially adjacent and are distributed throughout the polypeptide chain. The template is derived using the fixed positions for the main-chain and beta-carbon atoms in the test structure and selected stereochemical rules. The focus of this paper is on the use of two packing criteria: avoidance of steric overlap and complete filling of available space. The program also notes potential polar group interactions and disulfide bonds as well as possible burial of formal charges. Central to the algorithm is the side-chain rotamer library. In an update of earlier studies by others, we show that 17 of the 20 amino acids (omitting Met, Lys and Arg) can be represented adequately by 67 side-chain rotamers. A list of chi angles and their standard deviations is given. The newer, high-resolution, refined structures in the Brookhaven Protein Data Bank show similar mean chi values, but have much smaller deviations than those of earlier studies. This suggests that a rotamer library may be a better structural approximation than was previously thought. In using packing constraints, it has been found essential to include all hydrogen atoms specifically. The "unified atom" representation is not adequate. The permitted rotamer sequences are severely restricted by the main-chain plus beta-carbon atoms of the test structure. Further restriction is introduced if the full set of atoms of the external residues are held fixed, the full-chain model. The space-filling requirement has a major role in restricting the template lists. The preliminary tests reported here make it appear likely that templates prepared from the currently known core structures will be able to discriminate between these structures. The templates should thus be useful in deciding whether a sequence of unknown tertiary structure fits any of the known core classes and, if a fit is found, how the sequence should be aligned in three dimensions to fit the core of that class.(ABSTRACT TRUNCATED AT 400 WORDS)

This article reviews the results of 43 studies published since 1966 that provided estimates for the prevalence of pervasive developmental disorders (PDDs), including autistic disorder, Asperger disorder, PDD not otherwise specified, and childhood disintegrative disorder. The prevalence of autistic disorder has increased in recent surveys and current estimates of prevalence are around 20/10,000, whereas the prevalence for PDD not otherwise specified is around 30/10,000 in recent surveys. Prevalence of Asperger disorder is much lower than that for autistic disorder and childhood disintegrative disorder is a very rare disorder with a prevalence of about 2/100,000. Combined all together, recent studies that have examined the whole spectrum of PDDs have consistently provided estimates in the 60-70/10,000 range, making PDD one of the most frequent childhood neurodevelopmental disorders. The meaning of the increase in prevalence in recent decades is reviewed. There is evidence that the broadening of the concept, the expansion of diagnostic criteria, the development of services, and improved awareness of the condition have played a major role in explaining this increase, although it cannot be ruled out that other factors might have also contributed to that trend.