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ECMA Standard 335, “Common Language Infrastructure (CLI)”, was published in December 2001. According to Partition I, Section 1, it defines the Common Language Infrastructure (CLI) in which applications written in multiple high level languages may be executed in different system environments without the need to rewrite the application to take into consideration the unique characteristics of those environments. The standard is specified in natural language. Given the limitations of natural language, it is difficult to write a specification free of ambiguity and potential contradiction. Therefore, a formal model has been constructed in Z Notation of a subset of the Standard: the Common Type System (CTS) and many of the Common Language Specification (CLS) Rules. The model provides a framework for reasoning about the CTS and the CLS Rules, and establishes a base on which further areas of the Standard can be formalized. In the process of writing the formalisms, possible contradictions and ambiguities have been identified, which are discussed either in the body of the text or in the Appendices. In many cases the authors are confident that they have correctly interpreted the intention of the Standard;where they are not confident, the problems are described in Appendix E, Unresolved Questions.

The incidence of opportunistic yeast infections in humans has been increasing over recent years. These infections are difficult to treat and diagnose, in part due to the large number and broad diversity of species that can underlie the infection. In addition, resistance to one or several antifungal drugs in infecting strains is increasingly being reported, severely limiting therapeutic options and showcasing the need for rapid detection of the infecting agent and its drug susceptibility profile. Current methods for species and resistance identification lack satisfactory sensitivity and specificity, and often require prior culturing of the infecting agent, which delays diagnosis. Recently developed high-throughput technologies such as next generation sequencing or proteomics are opening completely new avenues for more sensitive, accurate and fast diagnosis of yeast pathogens. These approaches are the focus of intensive research, but translation into the clinics requires overcoming important challenges. In this review, we provide an overview of existing and recently emerged approaches that can be used in the identification of yeast pathogens and their drug resistance profiles. Throughout the text we highlight the advantages and disadvantages of each methodology and discuss the most promising developments in their path from bench to bedside., The authors discuss the current status of the use of high-throughput (-omics) technologies on the diagnostics of yeast infections.

Background—Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. Aims—To assess the short and long term response to GH therapy in patients with Noonan syndrome. Methods—Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this postmarketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. Results—Data on 66 patients (54 males) were available for study.At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from ˛2.9 pretreatment to ˛2.6 after one year and ˛2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range ˛1.1 to 6.5 cm). Conclusions—GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of eVect;initial indications are that final height is not improved substantially in most patients. (Arch Dis Child 2001;84:440‐443)

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

Extensive observations by the authors in Arizona have shown that the honey bee and several species of solitary bees in the genus Melissocles are the only abundant, active and efficient pollinators of cotton. Melissocles bees nest within cotton fields among the rows of cotton and the females apparently prefer cotton pollen, so that these bees are potentially important cotton pollinators. This paper presents recognition characters for the important species of Melissodes in Arizona, records of distribution and host plants, and some observations on nesting and work habits.

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There is a considerable interest in native bees as pollinating agents of alfalfa in Arizona to supplement honey bees. Collections of bees in alfalfa have been made during the past two years and there appears to be a relatively few species of native bees which are encountered. A key to the genera of the bees appears below with some information on the distribution and host plant records of some of the more important species.

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This paper discusses the life hi story and nesting habits of a leaf-cutter bee, Megachile (Eutricharaea) concinna Smith, in southern Arizona. A closely related species, Megachile (Eutricharaea) rotundata (Fabricius), is a urnful pollinator of alfalfa in the Pacific Iorthwest and in the lntermountain Region. Biological observations of this species were reported by Stephen and Torchio (1961) and artificial nesting sites and their management by Stephen (1961 and 1962), and Bohart (1962).

Candida glabrata is a pathogenic yeast of increasing medical concern. It has been regarded as asexual but is more closely related to sexual yeasts than other Candida species. It is shown here that the C. glabrata genome contains many genes apparently involved in sexual reproduction., Background Candida glabrata is a pathogenic yeast of increasing medical concern. It has been regarded as asexual since it was first described in 1917, yet phylogenetic analyses have revealed that it is more closely related to sexual yeasts than other Candida species. We show here that the C. glabrata genome contains many genes apparently involved in sexual reproduction. Results By genome survey sequencing, we find that genes involved in mating and meiosis are as numerous in C. glabrata as in the sexual species Kluyveromyces delphensis, which is its closest known relative. C. glabrata has a putative mating-type (MAT) locus and a pheromone gene (MFALPHA2), as well as orthologs of at least 31 other Saccharomyces cerevisiae genes that have no known roles apart from mating or meiosis, including FUS3, IME1 and SMK1. Conclusions We infer that C. glabrata is likely to have an undiscovered sexual stage in its life cycle, similar to that recently proposed for C. albicans. The two Candida species represent two distantly related yeast lineages that have independently become both pathogenic and 'asexual'. Parallel evolution in the two lineages as they adopted mammalian hosts resulted in separate but analogous switches from overtly sexual to cryptically sexual life cycles, possibly in response to defense by the host immune system.

Background and objectives C. glabrata is a commensal found in the human genitourinary tract but under certain conditions this harmless colonization evolves to a mucosal infection and, in more serious cases, to disseminated mycosis. To thrive in the acidic vaginal tract C. glabrata has to cope with the presence of a competing com- mensal microbiota that restrains the overgrowth of pathogens by producing acetic and lactic acids, among other interference effects. The persistent emergence of C. glabrata strains resistant to currently used antifungals demands the implementation of novel therapeutic strategies based on non-conventional targets. Genes contributing to increase C. glabrata competitiveness in the vaginal tract by mediating tolerance to the organic acids found therein are a cohort of interest- ing, and yet unexplored, set of therapeutic targets. Thus, the objec- tive of this work is the identification of key genes/pathways/ mechanisms underlying survival of C. glabrata to acetic and/or lactic acids. In particular, the characterization of the involvement of a new signalling system, controlled by the putative transcription factor CgHaa1, in C. glabrata tolerance and response to acetic acid is aimed. Results and conclusions Elimination of CgHAA1 gene from C. glab- rata genome dramatically increased susceptibility of this pathogenic yeast to concentrations of acetic acid similar to those found in the vaginal tract. A transcriptomic analysis revealed that CgHaa1 impacted the expression of roughly 70% of the overall set of C. glab- rata genes that are activated in response to acetic acid stress, con- firming the crucial role of this transcriptional regulator in the control of genomic expression under these conditions. Functional clustering of the genes activated by CgHaa1 under acetic acid stress shows an enrichment of those involved in carbohydrate metabolism, transport, cell wall maintenance, regulation of internal pH and nucleic acid processing. The mechanisms by which the CgHaa1 pathway mediate tolerance to acetic acid in C. glabrata were further dissected, explor- ing a transcriptomics approach, being of notice the involvement of this regulatory system in the control of internal pH and in reducing the internal accumulation of the acid. In the presence of acetic acid CgHaa1 enhanced adhesion and colonization of reconstituted vaginal human epithelium by C. glabrata ,an in vitro model of vaginal infec- tion. Consistently, CgHaa1 expression exerted a positive effect over the expression of several adhesin-encoding genes and increased C. glabrara adherence to the extracellular matrix proteins fibronectin and vitronectin. On the overall the results obtained show similarities, but also remarkable differences, in the way by which the ScHaa1 and CgHaa1 pathways mediate tolerance to acetic acid in S. cerevisiae and in C. glabrata , indicating a ‘functional expansion’of the network in the later species. Further details on the evolution of this network from S. cerevisae to C. glabrata will be discussed. The role of the CgHaa1-pathway in the extreme acetic acid-tolerance exhibited by vaginal C. glabrata isolates will also be discussed, along with other uncovered mechanistic insights that were found to be on the basis of the acid tolerance phenotype exhibited by these isolates.

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