Low-dose IL-2 induces CD56bright NK regulation of T cells via NKp44 and NKp46.

Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (Tregs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (Teffs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-ß, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in Treg cells, which is dependent on the presence of CD56bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.

The pilin O-glycosylation pathway of pathogenic Neisseria is a general system that glycosylates AniA, an outer membrane nitrite reductase.

O-Glycosylation is emerging as a common posttranslational modification of surface exposed proteins in bacterial mucosal pathogens. In pathogenic Neisseria an O-glycosylation pathway modifies a single abundant protein, pilin, the subunit protein that forms pili. Here, we identify an additional outer membrane glycoprotein in pathogenic Neisseria, the nitrite reductase AniA, that is glycosylated in its C-terminal repeat region by the pilin glycosylation pathway. To our knowledge, this is the first report of a general O-glycosylation pathway in a prokaryote. We also show that AniA displays polymorphisms in residues that map to the surface of the protein. A frame-shift mutation abolishes AniA expression in 34% of Neisseria meningitidis strains surveyed, however, all Neisseria gonorrhoeae strains examined are predicted to express AniA, implying a crucial role for AniA in gonococcal biology.

Economic impact of early intervention in people at high risk of psychosis.

BACKGROUND: Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. METHOD: The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. RESULTS: Over the initial 12 months from presentation, the costs of the OASIS intervention were pound1872 higher than CAU. However, after 24 months they were pound961 less than CAU. CONCLUSIONS: This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

Optical diffraction analysis of petrographic thin sections.

Diffraction patterns that are highly reproducible, of useful quality, and consistent with the input generating them can be easily obtained with a microscope system. The input can be either a reduced photograph or a thin section. With two exceptions, the relationships between a thin section and its diffraction pattern produced by a petrographic microscope are the same as the relationships between a photographic input and its diffraction pattern produced by a conventional ODA system. The exceptions are that the diffraction patterns generated directly by the thin sections may be asymmetrical or, if the thin section is sufficiently heterogeneous, may be smeared. The microscope system is generally more useful than a conventional ODA system for the analysis of microfabric in thin sections. One can readily use the microscope system to analyze elements of widely varying spatial frequency simply by changing the objectives. The diffraction patterns can be magnified by changing to a higherpower ocular. In most cases the microscope-generated diffraction pattern transmits the useful spatial information in the thin section more completely than the conventionally produced diffraction pattern; the photographic inputs for the conventionally produced diffraction pattern emphasize lower-frequency spatial information. This property, combined with the microscope system's better response to twinning, makes the microscope more sensitive to commonly used microfabric elements. For the analysis of thin sections, a conventional ODA system is superior to the microscope system in only three cases. First, if one wants to analyze the entire thin section at one time, a conventional system must be used with a photographic input of the thin section. Second, if the thin section is extremely heterogeneous (crystallographically or mineralogically), the microscope-generated diffraction pattern may exhibit gross smearing even with the highestpower objectives available. Finally, the thin section may contain only elements of low spatial frequency that will not generate diffraction dots far enough radially from the central spot to be resolvable. More study will be needed to establish the precision of spatial frequency measurements from diffraction patterns generated directly by thin sections with the microscope system. Experiments with a variety of film types and sources of illumination will, in all likelihood, lead to a reduction in the exposure times used to record diffraction patterns with the microscope (9). A complete ODA system must have directional and frequency-filtering capabilities. In order to establish these capabilities for the microscope system, components will need to be designed and fabricated and the microscope body may have to be modified. The possibility of applying the microscope technique in reflected light on a real-time basis should be investigated. This would be a valuable tool in the quantitative analysis of microfracture initiation and propagation and the analysis of overall fabric changes during experimental deformation of rock both in situ and in the laboratory. The technique presented here can be used with a less expensive microscope, if it has a focusable Bertrand lens. Our experiments with relatively inexpensive microscopes indicated that the only major problem is alignment of the illuminating system (light-filter-condenser).

A case of aripiprazole and tardive dyskinesia.

This is a case report of a 24-year-old African lady, who developed symptoms of tardive dyskinesia (TD) following 9 months of treatment with aripiprazole 15 mg. She has no family history of mental illness, not used illicit substances and has a medical diagnosis of idiopathic hypertension which is well controlled. The patient has an 18-month history of paranoid schizophrenia with three psychotic episodes, one severe enough to warrant admission. Upon discontinuation of aripiprazole and switch to quetiapine, the symptoms of TD disappeared rapidly. A PubMed search revealed one previous case report of aripiprazole and TD. The authors recommend maintaining vigilance regarding all possible side-effects irrespective of the type of antipsychotic being used.

Cytology and outcome of LSIL: cannot exclude HSIL compared to ASC-H.

OBJECTIVE: The cytological features associated with clinical outcome of 'LSIL cannot exclude HSIL (LSIL-H)' in comparison with 'atypical squamous cells cannot exclude HSIL (ASC-H)' are incompletely described. METHODS: LSIL-H and ASC-H Pap tests reported in a regional laboratory during a 13-month period were reviewed by two pathologists. Cytological features suspicious for HSIL were evaluated against a check list of 52 atypical features. All histology over 2 years of follow up for tests reclassified as LSIL-H and ASC-H was retrieved to determine clinical outcome. Atypical cytological features were correlated with outcome. RESULTS: The review yielded 89 LSIL-H and 86 ASC-H. The highest ranked atypical cytological feature in each group was increased nuclear cytoplasmic ratio. Clinical outcome was positive (CIN II/III or AIS) in 44 (49%) LSIL-H and 33 (38%) ASC-H. Round (P = 0.02) and naked nuclei (P = 0.009) were significant correlates of outcome amongst LSIL-H tests, but no feature correlated with outcome in the ASC-H group. CONCLUSIONS: LSIL-H is different to ASC-H because of the 11% higher frequency of a positive outcome and the cytological features associated with outcome.

First detection of CTX-M-28 in a Tunisian hospital from a cefotaxime-resistant Klebsiella pneumoniae strain.

A cefotaxime-resistant Klebsiella pneumoniae ML4313 was obtained from a patient from intensive care unit of Military hospital in Tunisia. This strain was resistant to beta-lactams, aminoglycosides, quinolones and phenicols, and tetracyclines. It was identified as producer of extended-spectrum beta-lactamases (ESBL) by double-disk synergy test between amoxicillin-clavulanate and cefotaxime, ceftriaxone, ceftazidime and aztreonam. The ESBL was identified as CTX-M-28 by sequencing of PCR products and by isoelectric focusing. The ESBL resistance was transferred by a 50kb plasmid. CTX-M-28 is closely related to CTX-M-15. This is the first description of this enzyme in Tunisia.

Early intervention services for psychosis in Ireland: are we there yet?

Early intervention in psychosis (EIP) services are now a priority for Ireland's Health Service Executive (HSE). A Model of Care for EIP services has been completed after wide consultation. It has just been launched by the Minister for Mental Health and the aim now is to roll out EIP services throughout the country. The Model of Care outlines the rational, configuration, resources, governance, and quality assurance required to operate EIP services. Two models are recommended. The first is a Hub & Spoke service model for rural and smaller urban areas. The second is a Stand-Alone service model for large urban and metropolitan areas. Introducing EIP services is going to be a challenge but there are plenty of good examples overseas. They have been shown to greatly enhance local services' ability to meet the needs of people developing psychotic disorders. They bring with them better outcomes, service satisfaction and cost savings.

Attaining the age threshold for adolescent mental health services: factors associated with transition of care in the independent sector in Ireland.

OBJECTIVES: The transition from adolescent to adult mental health services (AMHS) is associated with disengagement, poor continuity of care and patient dissatisfaction. The aim of this retrospective and descriptive study was to describe the 'care pathways' in an independent mental health service when adolescents reach age 18 and to investigate the level of engagement of those who transitioned to independent AMHS. METHODS: This is a retrospective, naturalistic and descriptive study in design. All patients discharged from the St Patrick's Adolescent Mental Health Service aged 17 years and 6 months and older, during a 3-year period between January 2014 and December 2016, were included. Electronic records were used to collect socio-demographic and clinical details and to determine engagement rates in adolescents who transferred to independent adult services. RESULTS: A total of 180 patients aged over 17 years and 6 months were discharged from the adolescent service. Of these, 45.6% were discharged to their GP, 28.9% to public mental health services and 25.6% to independent mental health services. The majority who transitioned to independent AMHS went to a Young Adult Service, which had high engagement rates at 3 and 12 months post-transition. CONCLUSIONS: In this independent mental health service, less than half of adolescents who reach the transition age are referred onto AMHS. Engagement rates were found to be high among those referred on to a specialised young adult service.

Immunobiological role of llama heavy-chain antibodies against a bacterial beta-lactamase.

In 1993, a fraction of antibodies (Abs) devoid of L chain was found naturally occurring in the Camelidae. They were found to lack L chains, as well as the first constant heavy-chain domain (CH(1)) and therefore they were named "heavy-chain Abs" (HCAbs). Subsequent studies focused on the functional, structural and biochemical properties of recombinant variable fragments (rVHHs) of HCAbs. It was stated that rVHHs have an augmented capacity to interact with "partially hidden" epitopes, like enzymes active sites, and have an increased stability to thermal and chemical aggression. It has been suggested that these unconventional Abs could represent an evolutionary advantage, being more efficient than conventional Abs to inhibit microbial enzymes, and thus exerting a more protective immune response against pathogens. The present work focuses on the immunobiological role of HCAbs, in their capacity to inhibit microbial enzymes. Two animal models were selected, comprising a model for common vertebrates without HCAbs (rabbits), and a model for vertebrates with both conventional and unconventional Abs (Lama glama). A recombinant bacterial beta-lactamase (CTX-M-2) was selected as the microbial enzymatic antigen. After conventional immunization schedules, neither serum titers nor serum inhibitory capacity showed significant differences when rabbits and llamas were compared. These results indicate that the a priori assumption that the adaptive immune system of camelids could be better "prepared" to respond to bacterial enzymes because of the presence of HCAbs, is not always accurate. Furthermore, when the different llama antibody isotypes and subclasses were purified, it was demonstrated that the inhibitory capacity of total serum was due exclusively to IgG(1). HCAbs not only failed to inhibit CTX-M-2, but instead they activated its enzymatic activity. Altogether, these results indicate that the hypotheses extrapolated from the rVHHs properties need to be revised; the real role of HCAbs in vivo remains unknown, as well as their evolutionary cause.

The impact of a specialized inpatient and day patient group programme on clinical outcome in older adolescents and young adults with mental illness.

Introduction Effective transition from child and adolescent mental health services (CAMHS) to adult services is one of the main challenges currently facing child psychiatry today The Young Adult 1Programme (YAP) based at St. Patrick's University Hospital Dublin, is a group based day programme especially designed to meet the needs of younger people aged 18-25 and support them through this difficult period. Aims To examine the effectiveness of participation in YAP for young adults with mental illness. To determine whether participation in particular aspects of the programme prove more beneficial and what factors might be associated with outcome. METHOD: All patients enrolled in YAP between 1 September 2011 and 31 August 2012 were included in the study. Each patient was assessed using the Health of the Nation Outcome Scales (HONOS) and Global Assessment of Functioning (GAF) rating scale before beginning the programme and after discharge in order to evaluate improvement. The frequency of attendance at individual group sessions was recorded. Patient and illness variables were also recorded, for example demographics, diagnosis. RESULTS: A total of 101 service users were in enrolled in YAP during this 12-month period. Eight service users could not be used for analysis, as they did not have a complete data set, mostly due to failure to attend for discharge HONOS/GAF ratings Using a paired sample t-test, there is a significant reduction in HONOS: Mean df=1.3, s.d.=1.09 (95% CI=1.08-1.53), p<0.001 Using a paired sample t-test, there is a significant increase in GAF: Mean df=9.25, s.d.=7.69 (95% CI=7.66-10.83), p<0.001 Improvements in HONOS and GAF scores are significantly correlated with better attendance at the programme (p<0.04, <0.00 respectively). CONCLUSION: More attendance at YAP sessions correlates with better improvement in both HONOS and GAF rating scores.

[Genetic environment of CTX-M-2 in Klebsiella pneumoniae isolates from hospitalized patients in Uruguay]. / Entorno genético de CTX-M-2 en aislamientos de Klebsiella pneumoniae provenientes de pacientes hospitalizados en Uruguay.

We studied two CTX-M-2-producing Klebsiella pneumoniae clinical strains, K96005 and K13, isolated from hospitalized patients in Uruguay, during 1996 and 2003, respectively. The genomic surroundings of bla(CTX-M-2) were characterized by PCR-mapping and DNA sequencing. Our results show that blaCTX-M-2 is included in a complex class-1 integron (InK13), associated with an orf513 in both isolates. The genetic array of the integron, aac(6')-lb, bla(OxA,2), orfD (gene cassette region), associated with an orf513-bla(CTX-M-2), seems to be widely disseminated over the Rio de la Plata region.

Intervening early in bipolar disorder in young people: a review of the clinical staging model.

Bipolar disorder (BPD) essentially has its onset during adolescence and early adulthood. It has the capacity to be highly disruptive, dislocating individuals from their normal developmental trajectory and potentially causing significant long-term co-morbidity and chronicity. At a societal level the burden created is greater than schizophrenia. This is not helped by the very substantial delays in its diagnosis and appropriate treatment. Thus, there is a clear rationale for intervening earlier and at a younger age. However, the field of early intervention in BPD is in its infancy. One approach that conceptually provides a basis for early intervention is the Clinical Staging Model (used widely in general medicine). This article outlines how this model helps in an understanding of the emerging stages of BPD. It also summarises the interventions that might be appropriately introduced if a person progresses from an early to a late stage of the illness. Early intervention has a well-established record in psychotic disorders. If it can be realised for BPDs, then it may hold out hope of better outcomes for the next generation of young people at risk.

Salts of the two-coordinate homoleptic manganese(I) dialkyl anion [Mn{C(SiMe3)3}2](-) with quenched orbital magnetism.

The reduction of Mn{C(SiMe3)3}2 with KC8 in the presence of crown ethers yielded the d(6), Mn(I) salts [K2(18-crown-6)3][Mn{C(SiMe3)3}2]2 and [K(15-crown-5)2][Mn{C(SiMe3)3}2], that have near-linear manganese coordination but almost completely quenched orbital magnetism as a result of 4s-3dz(2) orbital mixing which affords a non-degenerate ground state.

Binding of O-alkyl derivatives of serotonin at human 5-HT1D beta receptors.

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D beta receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1D beta affinity (Ki = 1 nM) and selectivity (> 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1D beta Ki = 2.3 nM) but with greater (i.e, 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or beta-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1D beta versus 5-HT1D alpha sites; nevertheless, compounds 10 (recently shown to have as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.

An evaluation of currently available methods for plasma fibrinogen.

Fibrinogen levels in a variety of clinical plasma samples were assessed concurrently by several methods. Technics that appeared to provide the best improvements over the basic varieties of methods for fibrinogen assay were used. Results were correlated against a reference method based on Ancrod clottable fibrinogen and calibrated by ultraviolet absorbance with alkaline solutions of carefully dried fibrin standard. The best correlations with the reference method were achieved by an immunologic method using the Centrifichem principle and by heat precipitation with quantitation by packing in microhematocrit tubes. A modified clot opacity method also gave acceptable results. The turbidimetric ammonium sulfate and sodium sulfite precipitation methods correlated less well with the reference method, and in particular, the sodium sulfite technic gave high apparent fibrinogen levels with jaundiced plasmas. Neither of the turbidimetric methods were useful for fibrinogen levels below 50 mg/dl. The thrombin time method showed excellent sensitivity to fibrinogen, even at very low fibrinogen levels, but did not correlate well with the reference method.

The genetics of glycosylation in Gram-negative bacteria.

In recent years there has been a dramatic increase in reports of glycosylation of proteins in various Gram-negative systems including Neisseria meningitidis, Neisseria gonorrhoeae, Campylobacter jejuni, Pseudomonas aeruginosa, Escherichia coli, Caulobacter crescentus, Aeromonas caviae and Helicobacter pylori. Although this growing list contains many important pathogens (reviewed by Benz and Schmidt [Mol. Microbiol. 45 (2002) 267-276]) and the glycosylations are found on proteins important in pathogenesis such as pili, adhesins and flagella the precise role(s) of the glycosylation of these proteins remains to be determined. Furthermore, the details of the glycosylation biosynthetic process have not been determined in any of these systems. The definition of the precise role of glycosylation and the mechanism of biosynthesis will be facilitated by a detailed understanding of the genes involved.

Gallium-boron donor-acceptor bonds.

Examples of compounds with gallium-boron donor-acceptor bonds, HC[MeC(2,6-pri2C6H3)N]2Ga-->B(C6F5)3 3 and (eta 5-C5Me5)Ga-->B(C6F5)3 4 have been prepared by treatment of the free gallanediyls with B(C6F5)3; the structures of both compounds were determined by X-ray crystallography.

Cognitively oriented psychotherapy for early psychosis (COPE): a 1-year follow-up.

OBJECTIVES: Cognitively oriented psychotherapy for early psychosis (COPE) is aimed at facilitating the adjustment of the person, and at preventing or alleviating secondary morbidity in the wake of the first psychotic episode. DESIGN: A total of 80 people participated in the initial trial and completed assessments on a range of outcome measures. Post-treatment assessment results from a non-randomized controlled trial of COPE have been previously reported. The present paper describes the results obtained from 51 patients who attended a follow-up assessment 1 year subsequent to the end-of-treatment assessment. METHOD: The 51 patients formed three groups: (1) those who were offered and accepted COPE; (2) those who were offered COPE but refused it, and continued to receive other services from the Early Psychosis Prevention and Intervention Centre (EPPIC) (refusal subjects); and (3) those who were offered neither COPE nor any other continuing treatment from EPPIC (control subjects). RESULTS: At 1-year follow-up, there was only one significant difference and this was between the COPE and refusal groups on the Integration/Sealing Over (I/SO) measure (p = .008). End-of-treatment differences were mostly sustained over the 1-year follow-up period. When the complete sample of 80 was considered, there were no differences between the three groups in terms of hospital admissions, community episodes, or time taken to first in-patient re-admission. CONCLUSIONS: The study was weakened by the poor follow-up rates in the two control groups. This reduced power to detect differences between groups on the seven major measures. However, the relapse data gathered on the complete set of 80 patients were discouraging and suggest that the present formulation of COPE does not confer any advantage to those patients receiving the therapy over those not receiving the therapy.