bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sufficient statistics and expectation maximization algorithms in phylogenetic tree models
Authors: Kiryu Hisanori 
Published: July 2011

AbstractMotivation: Measuring evolutionary conservation is a routine step in the identification of functional elements in genome sequences. Although a number of studies have proposed methods that use the continuous time Markov models (CTMMs) to find evolutionarily constrained elements, their probabilistic structures have been less frequently investigated.Results: In this article, we investigate a sufficient statistic for CTMMs. The statistic is composed of the fractional duration of nucleotide characters over evolutionary time, Fd, and the number of substitutions occurring in phylogenetic trees, Ns. We first derive basic properties of the sufficient statistic. Then, we derive an expectation maximization (EM) algorithm for estimating the parameters of a phylogenetic model, which iteratively computes the expectation values of the sufficient statistic. We show that the EM algorithm exhibits much faster convergence than other optimization methods that use numerical gradient descent algorithms. Finally, we investigate the genome-wide distribution of fractional duration time Fd which, unlike the number of substitutions Ns, has rarely been investigated. We show that Fd has evolutionary information that is distinct from that in Ns, which may be useful for detecting novel types of evolutionary constraints existing in the human genome.Availability: The C++ source code of the ‘Fdur’ software is available at http://www.ncrna.org/software/fdur/Contact: kiryu-h@k.u-tokyo.ac.jpSupplementary information: Supplementary data are available at Bioinformatics online.
Epipelagic fish distributions in relation to thermal fronts in a coastal upwelling system using high-resolution remote-sensing techniques
Authors: Reese Douglas C. , O'Malley Robert T. , Brodeur Richard D. , Churnside James H. 
Published: July 2011

Abstract
Reese, D. C., O'Malley, R. T., Brodeur, R. D., and Churnside, J. H. 2011. Epipelagic fish distributions in relation to thermal fronts in a coastal upwelling system using high-resolution remote-sensing techniques. – ICES Journal of Marine Science, 68: 1865–1874. Coastal upwelling systems are characterized by substantial spatial and temporal variability with respect to surface conditions, with fauna patchily distributed and high abundances in localized areas. Examining habitat associations on finer spatial scales than previous studies have been able to achieve would advance the understanding of important marine coastal ecosystems. This study evaluates the spatial and temporal relationships of single fish and fish schools with sea surface temperature (SST) fronts in the northern California Current upwelling system, using lidar (light detection and ranging) from an aircraft to sample surface waters over the continental shelf. High-resolution data were collected on the distribution of surface nekton and SST, then the locations of fish were analysed with respect to their proximity to SST fronts using GIS spatial analyses. Both fish schools and solitary fish were located significantly closer to fronts than would be expected by chance. The association of fish to fronts varied with the progression of the upwelling season such that fish associated less with fronts under stronger upwelling conditions. The relationships observed indicate the importance of thermal features to fish as a habitat component in a variable upwelling environment and have implications for management and conservation.
The ups and downs of working with industry to collect fishery-dependent data: the Irish experience
Authors: Lordan Colm , Ó Cuaig Macdara , Graham Norman , Rihan Dominic 
Published: July 2011

Abstract
Lordan, C., Ó Cuaig, M., Graham, N., and Rihan, D. 2011. The ups and downs of working with industry to collect fishery-dependent data: the Irish experience. – ICES Journal of Marine Science, 68: 1670–1678. Working with the fishing industry to collect fishery-dependent data for scientific and advisory purposes is essential in most countries, but despite the many advantages of working with fishers, it is not without challenges. The objectives and the ups and downs of 16 recent projects in Ireland are described, and four case studies are discussed in detail. Some common themes that characterize both successful and unsuccessful experiences are identified. One critical aspect is industry's sometimes unrealistic time-horizons and expectations when engaging in scientific data collection. Detailed communication of objectives, procedures, results, and relevance not only to industry representatives, but also to vessel owners and crew, is required throughout the life cycle of a project. For some projects, there is a clear need to include incentives in the design, but for others this is less critical. The critical needs for ongoing quality control and assurance, validation of data, and appropriate project design are discussed, along with the link between successful management systems and participatory research. Finally, comment is provided on how the expected reforms of the EU's Common Fisheries Policy will place new demands on joint research.
Phaeochromocytomas, paragangliomas, and neuroblastoma
Authors: Mackenzie Isla S. , Brown Morris J. 
Published: July 2011

Phaeochromocytomas are rare neuroendocrine tumours of neural crest origin, which often produce excess catecholamines (1). Although usually arising from the chromaffin cells of the adrenal medulla, phaeochromocytomas may also arise at other sites of sympathetic or parasympathetic chromaffin tissue anywhere from the base of the skull to the pelvis. Extra-adrenal phaeochromocytomas are called paragangliomas. Some patients with phaeochromocytoma or paraganglioma present with the classical triad of symptoms of headaches, palpitations, and sweating but many others present with less specific features such as hypertension or with an unidentified mass lesion.

Owing to the rarity of the condition and the relatively nonspecific symptoms with which it often presents, it is not unusual for several years to pass from symptom onset until the diagnosis of phaeochromocytoma is made. However, the consequences of not finding a phaeochromocytoma can be severe and may even result in death. In fact, in one study, around 50% of cases of phaeochromocytoma found at post mortem were unsuspected during life. Interestingly, a former US President, Dwight Eisenhower, was found to have a 1.5 cm adrenal phaeochromocytoma at post mortem, which was undiagnosed during life despite a history of severe hypertension and headaches (2). Patients with untreated phaeochromocytoma are at risk of the cardiovascular consequences of catecholamine surges, including hypertensive emergencies, intracerebral haemorrhage, and acute heart failure. Approximately 10% of phaeochromocytomas are malignant and some represent part of familial syndromes. The genetic basis of many phaeochromocytomas is becoming increasingly apparent as more mutations are found.
Glucocorticoid resistance—a defect of the glucocorticoid receptor
Authors: van Rossum Elisabeth F. C. , Lamberts Steven W. J. 
Published: July 2011

The first case of glucocorticoid resistance was reported in 1976 by Vingerhoeds et al. (1). The patient was suffering from hypercortisolism with none of the tissue effects of Cushing’s disease. Further evaluation revealed that the ligand-binding affinity of the glucocorticoid receptor (GR) was diminished. His son and nephew were mildly affected and their GR also showed a reduced hormone affinity, although this was to a lesser extent. Later, the GR gene of the index patient was sequenced and showed a homozygous mutation at position 2054, yielding a valine for aspartic acid substitution at amino acid residue 641 (2). The other two family members appeared to be heterozygous carriers of the same mutation, which can explain their milder clinical picture. Since then, other patients with mutations in the GR gene leading to the syndrome of generalized glucocorticoid resistance have been described (Table 5.8.1) (18).

Familial glucocorticoid resistance is a rare disease, characterized by reduced cortisol action at the tissue level, which is compensated for by elevation of ACTH levels, resulting in an increase of adrenal steroids (glucocorticoids, androgens, mineralocorticoids) (18). It is rather unfamiliar and may confuse clinicians, since the signs and symptoms can be nonspecific. This syndrome has an autosomal recessive or dominant mode of inheritance.
Familial glucocorticoid deficiency
Authors: Hughes Claire , Metherell Louise , Clark Adrian J.L. 
Published: July 2011

Familial glucocorticoid deficiency (FGD), also known as isolated glucocorticoid deficiency or hereditary unresponsiveness to ACTH, is a rare, genetically heterogeneous autosomal recessive disorder. It is characterized by resistance of the adrenal cortex to ACTH, resulting in adrenal failure with isolated glucocorticoid deficiency. Mineralocorticoid production by the adrenal gland remains near normal.

Patients with FGD usually present in early childhood with symptoms relating to cortisol deficiency, including hypoglycaemia, jaundice, recurrent infection, and failure to thrive. Patients are hyperpigmented due to grossly elevated ACTH levels.

FGD was first described in 1959 by Shepard et al. who reported two sisters as having Addison’s disease without hypoaldosteronism (1). Subsequently, a number of patients were reported with an inherited form of adrenal insufficiency also without hypoaldosteronism (2–5). In contrast to Addison’s disease (see Chapter 5.9), FGD is a genetic disorder resulting from mutations in genes encoding essential proteins involved in the early response to ACTH.
Neuroendocrine tumour markers
Authors: Ramachandran R. , Dhillo W. 
Published: July 2011

Neuroendocrine cells occur either singly or in small groups in a variety of tissues and organs. Although morphologically and embryologically diverse, they are characterized by a number of unifying features. They have dense core secretory vesicles in the cytoplasm and hormone receptors on the cell membranes. There is evidence of prohormone activity within the cells and they synthesize, store, and secrete hormones. In addition, neuroendocrine cells possess an ability to take up and decarboxylate amine precursors.

Components of this diffuse endocrine system are particularly prominent in the gastrointestinal tract, pancreas, C cells of the thyroid, adrenal medulla, parathyroid tissue, respiratory tract, skin, and genitourinary system. Neuroendocrine tumours (NETs) are known to occur in all these tissues.

Historically, the diagnosis of NET was made on the basis of characteristic histological findings. The significantly worse prognosis in advanced disease and the availability of multiple therapeutic options have highlighted the need for robust tumour markers that can be used both for diagnosis and follow-up. Currently, a number of normal and abnormal forms of peptides, biogenic amines, and hormones, secreted by NETs, are routinely measured as markers of disease.

An ideal tumour marker would be one that is secreted exclusively by the tumour cells and is useful (1) for screening and differential diagnosis of NETs; (2) as a prognostic indicator; (3) as an estimate of tumour burden; and (4) as a surveillance tool. Although none of the currently available markers completely fits the paradigm for an ideal tumour marker, when measured in conjunction with each other, they are useful not only for making a diagnosis but also for monitoring response to therapy and in surveillance post-remission.
Genetics of type 1 diabetes mellitus
Authors: Savage David A. , Bain Stephen C. 
Published: July 2011

Type 1 diabetes, previously known as insulin-dependent diabetes mellitus, is a common chronic T-cell-mediated disease in which there is selective autoimmune destruction of the insulin-producing β‎ cells of the pancreas. Although the mechanisms underlying this process are not fully understood, type 1 diabetes occurs as a result of complex interactions between multiple genes (reviewed in references 1–3) and environmental influences, which may both promote and protect against disease. Type 1 diabetes clusters in some families, but with no distinct pattern of inheritance. The concordance rates in monozygotic twins for type 1 diabetes can reach 50%, compared to 6% for dizygotic twins. The sibling recurrence risk ratio (λ‎s) (risk to siblings ÷ risk to general population) value for type 1 diabetes is 15 (6.0 ÷ 0.4 or 6% ÷ 0.4%), and twin studies suggest that 80% to 85% of familial aggregation is accounted for by genes. Type 1 diabetes has been noted to coexist with other autoimmune diseases—notably, Graves’ disease and coeliac disease—in certain families, implying the involvement of common autoimmune pathways.

Improved understanding of the so-called ‘allelic architecture’ (the identity of disease-associated gene variants, their frequencies, and size of the risk conferred by each variant) and biological pathways involved in type 1 diabetes is expected to facilitate the identification of new therapeutic targets for the development of new treatments. DNA biomarkers could also assist risk prediction at a population level. This is clinically relevant since individuals can survive with only 20% intact β‎-cell mass, and the time to reach this level of destruction can be considerably delayed in some individuals, offering a window of opportunity for intervention therapy. Furthermore, clinical trials should be improved by only focusing on those patients at highest risk of developing type 1 diabetes.

Early prediction, improved treatments, and, ultimately, prevention of type 1 diabetes are major goals because incidence rates are increasing. A recent study by the EURODIAB Study Group, involving 20 population-based registries across 17 European countries, has assessed incidence trends in children diagnosed with type 1 diabetes under the age of 15 between 1989 and 2003: an overall increase of 3.9% per year was reported, and, in the under 5 age group, an increase of 5.4% per year was observed (4).
Immunology of type 1 diabetes mellitus
Authors: Peakman Mark 
Published: July 2011

The concept that the pathological hallmark of type 1 diabetes—namely, irreparable damage to β‎ cells—is the result of an autoimmune process has gained sustained credence since it was first intimated in the 1970s. Forty years on, a robust set of criteria can be applied to settle this important question. As a result of numerous, reproducible research findings (Table 13.2.3.1), there is now an overwhelming case to support the assertion that type 1 diabetes is an autoimmune disease.

Perhaps the most persuasive evidence is provided by the case reports of diabetes arising in recipients of bone marrow from patients with type 1 diabetes (1, 2). In these cases, the recipients underwent bone marrow ablation as part of the treatment for their underlying condition (e.g. relapsed haematological cancers) that effectively removed all autologous innate and adaptive immune cells. To reconstitute their immune system, they then received bone marrow from a sibling with type 1 diabetes. They developed the disease themselves some years later. It is hard to argue against the proposal that immune cells transferred in the bone marrow inoculum were responsible for β‎ cell destruction. Indeed, current practice in these circumstances is to ensure immune depletion of any mature T lymphocytes that may be present in the transplanted bone marrow using specific monoclonal antibodies. This successfully circumvents the problem—and also provides clear evidence for the pivotal role for T lymphocytes in causing β‎ cell damage.

It should be noted that the overwhelming majority of patients with type 1 diabetes—especially those inhabiting the Western, developed world—have evidence of the underlying autoimmune processes, as discussed in this chapter. However, there is a recognition that type 1 diabetes may be heterogeneous, as, in some patients, evidence of autoimmunity is lacking (WHO diabetes classification type 1B). In Japan, a fulminant form of diabetes has been described as representing 15–20% of type 1 disease (15). Presentation is characterized by a high prevalence of preceding common cold-like and gastrointestinal symptoms, a near-normal level of HbA1c (despite very high plasma glucose levels and ketoacidosis), raised serum

pancreatic enzyme levels, and absent C-peptide—but only rarely any evidence of autoantibodies against islet cell autoantigens (16). Some cases of type 1 diabetes arising in sub-Saharan Africa have also been described as lacking evidence of autoimmunity against islet cells (see Chapter 13.4.3.4); however, these data require clarification, since it is known that the autoantibodies decline and may disappear from the circulation soon after diagnosis, making retrospective classification of cohorts with established disease highly problematic (17). Future studies in these locations will need to establish evidence of autoimmunity at diagnosis in currently equivocal situations, using the most comprehensive, up-to-date range of serological markers (see Table 13.2.3.2, below), as well as to establish the clinical and immunogenetic features of the disease.
Genetics of severe insulin resistance
Authors: Semple Robert K. , Savage David B. , O’Rahilly Stephen 
Published: July 2011

As the prevalence of obesity burgeons, so the prevalence of insulin resistance follows. A small minority of patients have severe insulin resistance without obesity. These patients, while not contributing

significantly to the general prevalence of diabetes, often harbour pathogenic single gene defects affecting insulin signalling or adipose tissue function. Clinical history and examination may offer strong clues to the presence of severe insulin resistance, but laboratory confirmation should usually be sought. Biochemical diagnostic thresholds for severe insulin resistance are arbitrary, and should, ideally, be defined relative to BMI-adjusted population normal ranges (Fig. 13.3.5.1). However, one set of approximate diagnostic criteria is as follows:

◆ non-diabetic and BMI under 30 kg/m2—fasting insulin above 150 pmol/l OR peak insulin on oral glucose tolerance testing above 1500 pmol/l

◆ absolute insulin deficiency and BMI under 30 kg/m2—exogenous insulin requirement above 3 U/kg/day

◆ partial β‎ cell decompensation and/or BMI over 30 kg/m2—insulin levels are difficult to interpret in the context of obesity, while, in diabetes, glucotoxicity, impaired islet function, and a combination of endogenous and exogenous insulin in the circulation confuse the biochemical picture. In this setting, the clinical history and features such as acanthosis nigricans assume particular importance in making a diagnosis of likely monogenic severe insulin resistance, with subjective clinical judgement often required.
A national audit of pollen immunotherapy for children in the United Kingdom: patient selection and programme safety
Authors: Vance G. H. S. , Goldring S. , Warner J. O. , Cox H. , Sihra B. , Hughes S. , Gardner J. , North J. , Roberts G. , Proudfoot C. A. , Clarke A. , Luyt D. K. , Gillies D. , Fox A. T. 
Published: July 2011

SummaryBackground
Specific immunotherapy (SIT) is an effective treatment for grass and/or tree pollen‐induced severe allergic rhinoconjunctivitis. However, there are limited detailed data on the use of immunotherapy in children in the United Kingdom.Objectives
We audited NHS paediatric practice against current national guidelines to evaluate patient selection, SIT modalities and adverse events (AEs).Methods
Paediatricians offering pollen SIT were identified through the British Society of Allergy and Clinical Immunology Paediatric Allergy Group (BSACI‐PAG) and the database of SIT providers compiled for the Royal College of Physicians and Royal College of Pathologists 2010 joint working group. Standardized proformas were returned by 12 of 20 centres (60%), including 12 of 14 centres offering subcutaneous immunotherapy (SCIT) (85%).Results
Three hundred and twenty‐three children, with mean age 11 years at initiation (69% boys), had undergone 528 SIT cycles (SCIT 31%) over 10 years. Fifty‐five percent of all patients had asthma. Among SCIT programmes 24.5% patients had perennial (± seasonal) asthma; 75.6% of asthmatics undertaking SCIT had treatments at BTS/SIGN step 2 or above. AEs occurred frequently (50.4% of all SIT cycles) but were mild. In sublingual immunotherapy (SLIT) treatment, local intraoral immediate reactions were most common (44.9% SLIT cycles), as compared with delayed reactions around the injection site in SCIT (28.3% SCIT cycles). An asthma diagnosis had no impact on the number of cycles with AEs, or the severity reported. Few cycles (2.9%) were discontinued as a result of AE(s).Conclusions and Clinical Relevance
Pollen SIT is available across England, though small numbers of children are being treated. Current national guidelines to exclude asthmatic children in SIT programmes are not being adhered to by most specialist paediatric allergy centres. SCIT and SLIT has been well tolerated. Review of patient selection criteria is needed and may allow greater use of this therapeutic option in appropriate clinical settings. Cite this as: G. H. S. Vance, S. Goldring, J. O. Warner, H. Cox, B. Sihra, S. Hughes, J. Gardner, J. North, G. Roberts, C. A. Proudfoot, A. Clarke, D. K. Luyt, D. Gillies and A. T. Fox, Clinical & Experimental Allergy, 2011 (41) 1313–1323.
Mechanisms of immunotherapy to aeroallergens
Authors: Shamji M. H. , Durham S. R. 
Published: July 2011

SummaryAllergen immunotherapy is allergen‐specific, allergen dose‐ and time‐dependent and is associated with long‐term clinical and immunological tolerance that persists for years after discontinuation. Successful immunotherapy is accompanied by the suppression of numbers of T‐helper 2 (Th2) effector cells, eosinophils, basophils, c‐kit+mast cells and neutrophils infiltration in target organs, induction of IL‐10 and/or TGF‐β+Treg cells and increases in ‘protective’ non‐inflammatory blocking antibodies, particularly IgG4 and IgA2 subclasses with inhibitory activity. These events are accompanied by a reduction and/or a redirection of underlying antigen‐specific Th2‐type T cell‐driven hypersensitivity to the allergen(s) used for therapy. This suppression occurs within weeks or months as a consequence of the appearance of a population of regulatory T cells that exert their effects by mechanisms involving cell–cell contact, but also by the release of cytokines such as IL‐10 (increases IgG4) and TGF‐β (increases specific IgA). The more delayed‐in‐time appearance of antigen‐specific T‐helper 1 responses and alternative mechanisms such as Th2 cell anergy and/or apoptosis may also be involved. The mechanisms of sublingual immunotherapy are similar to those following a subcutaneous administration of allergen, whereas it is likely that additional events following antigen presentation in the sublingual mucosa and regional lymph nodes are involved. These insights have resulted in novel approaches and portend future biomarkers that may be surrogate or predictive of the clinical response to treatment. Cite this as: M. H. Shamji and S. R. Durham, Clinical & Experimental Allergy, 2011 (41) 1235–1246.