Group A streptococcal pharyngitis: A practical guide to diagnosis and treatment.

Group A Streptococcus (GAS) pharyngitis is a common clinical syndrome in primary care, yet controversy remains regarding the best approach to diagnosis and treatment, including the benefits of antibiotics. Children who are likely to have GAS pharyngitis based on history or physical examination should have a throat swab and, when positive, be treated with amoxicillin or penicillin. The disproportionate burden of acute rheumatic fever in Indigenous populations in Canada and special considerations for testing and treatment are discussed.

Immunopathogenesis of infectious bronchitis virus Q1 in specific pathogen free chicks.

The immunopathogenesis of avian coronavirus, infectious bronchitis virus (IBV) Q1, was investigated in specific pathogen free chicks. Following infection, chicks exhibited respiratory clinical signs and reduced body weight. Oropharyngeal (OP) and cloacal (CL) swabs were collected at intervals and found to be RT-PCR positive, with a greater number of partial-S1 amino acid changes noted in CL swabs compared to OP swabs. In tissue samples, IBV viral load peaked 9 days post infection (dpi) in the trachea and kidneys, and 14 dpi in the proventriculus. At 28 dpi, ELISA data showed that 63% of infected chicks seroconverted. There was significantly higher mRNA up-regulation of IFN-α, TLR3, MDA5, LITAF, IL-1ß and IL-6 in the trachea compared to the kidneys. Findings presented here demonstrate that this Q1 isolate induces greater lesions and host innate immune responses in chickens' tracheas compared to the kidneys.

Update on congenital cytomegalovirus infection: Prenatal prevention, newborn diagnosis, and management.

Cytomegalovirus (CMV) is the leading cause of congenital infection and the most common cause of non-genetic sensorineural hearing loss (SNHL) in childhood. Although most infected infants are asymptomatic at birth, the risk for SNHL and other neurodevelopmental morbidity makes congenital CMV (cCMV) a disease of significance. Adherence to hygienic measures in pregnancy can reduce risk for maternal CMV infection. The prompt identification of infected infants allows early initiation of surveillance and management. A multidisciplinary approach to management is critical to optimize outcomes in affected infants.

Quantifying Soft Tissue Artefacts and Imaging Variability in Motion Capture of the Fingers.

This study assessed the accuracy of marker-based kinematic analysis of the fingers, considering soft tissue artefacts (STA) and marker imaging uncertainty. We collected CT images of the hand from healthy volunteers with fingers in full extension, mid- and full-flexion, including motion capture markers. Bones and markers were segmented and meshed. The bone meshes for each volunteer's scans were aligned using the proximal phalanx to study the proximal interphalangeal joint (PIP), and using the middle phalanx to study the distal interphalangeal joint (DIP). The angle changes between positions were extracted. The HAWK protocol was used to calculate PIP and DIP joint flexion angles in each position based on the marker centroids. Finally the marker locations were 'corrected' relative to the underlying bones, and the flexion angles recalculated. Static and dynamic marker imaging uncertainty was evaluated using a wand. A strong positive correlation was observed between marker- and CT-based joint angle changes with 0.980 and 0.892 regression slopes for PIP and DIP, respectively, and Root Mean Squared Errors below 4°. Notably for the PIP joint, correlation was worsened by STA correction. The 95% imaging uncertainty interval was < ± 1° for joints, and < ± 0.25 mm for segment lengths. In summary, the HAWK marker set's accuracy was characterised for finger joint flexion angle changes in a small group of healthy individuals and static poses, and was found to benefit from skin movements during flexion.

Mental illness and the provision of mental health services in prisons.

Introduction: Around 11 million people are held in prisons internationally, and criminal justice systems are overburdened with a high prevalence of multiple psychiatric disorders. In England and Wales over 200 000 people enter prisons each year, and in many cases, this facilitates their first contact with mental health services. Sources of data: Research, evaluations, government reports and independent reviews. Areas of agreement: Screening, Triage, Assessment, Intervention and Re-integration (STAIR) are necessary components of prison mental health provision, offering an opportunity to improve the wellbeing of a complex population. Areas of controversy: There are serious problems with service provision across many parts of the world, with human rights abuses occurring in some States. Screening and service delivery models still require substantial development. In England and Wales, self-harm, self-inflicted deaths and violence are increasing. Growing points: Introducing comprehensive mental health models throughout prisons would offer a massive public health initiative, providing new services for the socially disadvantaged. A rights-based framework would be useful in ensuring systemic improvements, especially in low and middle-income countries. Areas timely for developing research: Mechanisms for screening and triage, specific interventions across a broad range of conditions, and practical re-integration models, should be submitted to research across international sites.

Interventions at the Transition from Prison to the Community for Prisoners with Mental Illness: A Systematic Review.

Prisoners have high rates of mental illness and the transition from prison to the community is a problematic time for the provision of mental health services and a range of negative outcomes have been identified in this period. A systematic review was conducted to identify interventions for prisoners with diagnosed mental health conditions that targeted this transition period. Fourteen papers from 13 research studies were included. The interventions identified in this review were targeted at different stages of release from prison and their content differed, ranging from Medicaid enrolment schemes to assertive community treatment. It was found that insurance coverage, and contact with mental health and other services can be improved by interventions in this period but the impact on reoffending and reincarceration is complex and interventions may lead to increased return to prison. There is a developing evidence base that suggests targeting this period can improve contact with community mental health and other health services but further high quality evidence with comparable outcomes is needed to provide more definitive conclusions. The impact of programmes on return to prison should be evaluated further to establish the effect of interventions on clinical outcomes and to clarify the role of interventions on reincarceration.

Mental health morbidity among people subject to immigration detention in the UK: a feasibility study.

AIMS: The UK has one of the largest systems of immigration detention in Europe.. Those detained include asylum-seekers and foreign national prisoners, groups with a higher prevalence of mental health vulnerabilities compared with the general population. In light of little published research on the mental health status of detainees in immigration removal centres (IRCs), the primary aim of this study was to explore whether it was feasible to conduct psychiatric research in such a setting. A secondary aim was to compare the mental health of those seeking asylum with the rest of the detainees. METHODS: Cross-sectional study with simple random sampling followed by opportunistic sampling. Exclusion criteria included inadequate knowledge of English and European Union nationality. Six validated tools were used to screen for mental health disorders including developmental disorders like Personality Disorder, Attention Deficit Hyperactivity Disorder (ADHD), Autistic Spectrum Disorder (ASD) and Intellectual Disability, as well as for needs assessment. These were the MINI v6, SAPAS, AQ-10, ASRS, LDSQ and CANFOR. Demographic data were obtained using a participant demographic sheet. Researchers were trained in the use of the screening battery and inter-rater reliability assessed by joint ratings. RESULTS: A total of 101 subjects were interviewed. Overall response rate was 39%. The most prevalent screened mental disorder was depression (52.5%), followed by personality disorder (34.7%) and post-traumatic stress disorder (20.8%). 21.8% were at moderate to high suicidal risk. 14.9 and 13.9% screened positive for ASD and ADHD, respectively. The greatest unmet needs were in the areas of intimate relationships (76.2%), psychological distress (72.3%) and sexual expression (71.3%). Overall presence of mental disorder was comparable with levels found in prisons. The numbers in each group were too small to carry out any further analysis. CONCLUSION: It is feasible to undertake a psychiatric morbidity survey in an IRC. Limitations of the study include potential selection bias, use of screening tools, use of single-site study, high refusal rates, the lack of interpreters and lack of women and children in study sample. Future studies should involve the in-reach team to recruit participants and should be run by a steering group consisting of clinicians from the IRC as well as academics.

Characteristics of prisoners with intellectual disabilities.

BACKGROUND: Previous studies have found high rates of intellectual disabilities (ID) in prison. However, little is understood about prisoners with ID. This study aimed to identify prisoners with ID and compare their characteristics with prisoners without neurodevelopmental disorders with regard to demographic profile, mental health, suicide risk and offences. METHOD: This was a descriptive, cross-sectional study carried out using face-to-face interviews with 240 participants in a London Category C prison. Standardised tools were used to assess prisoners for ID and mental disorder. RESULTS: The study identified 18 prisoners as having ID. Participants with ID were less likely to be from a black or minority ethnic background, be over 35 years of age or have any qualifications. They were more likely to have been single, homeless or unemployed before coming into prison. Prisoners with ID were significantly more likely to have mental health problems and 25% had thought about suicide in the last month and 63% had attempted suicide in the past. Prisoners with ID were also more likely to be housed in the vulnerable prisoners' wing and significantly more likely to have committed robbery than other prisoners. CONCLUSIONS: The findings confirm the presence of significant numbers of people with ID with high levels of mental illness in a male prison. Services across the CJS are required for this group, specifically, there is a need for raised awareness among those working in prison about ID and improved skills to recognise offenders with ID and address major gaps in current healthcare provision in prison.

Characterization of the Zebrafish Homolog of ß-Glucosidase 2: A Target of the Drug Miglustat.

The small-molecular compound miglustat (N-butyldeoxynojirimycin, Zavesca(®)) has been approved for clinical use in type 1 Gaucher disease and Niemann-Pick type C disease, which are disorders caused by dysfunction of the endosomal-autophagic-lysosomal system. Miglustat inhibits a number of enzymes involved in glycoconjugate and glycan metabolism, including ß-glucosidase 2 (GBA2), which is exceptionally sensitive to inhibition by miglustat. GBA2 is a glucosylceramide-degrading enzyme that is located on the plasma membrane/endoplasmic reticulum, and is distinct from the lysosomal enzyme glucocerebrosidase (GBA). Various strands of evidence suggest that inhibition of GBA2 contributes to the therapeutic benefits of miglustat. To further explore the pharmacology and biology of GBA2, we investigated whether the zebrafish homolog of GBA2 has similar enzymatic properties and pharmacological sensitivities to its human counterpart. We established that zebrafish has endogenous ß-glucosidase activity toward lipid- and water-soluble GBA2 substrates, which can be inhibited by miglustat, N-butyldeoxygalactonojirimycin, and conduritol B epoxide. ß-Glucosidase activities with highly similar characteristics were expressed in cells transfected with the zebrafish gba2 cDNA and in cells transfected with the human GBA2 cDNA. These results provide a foundation for the use of zebrafish in screening GBA2-targeting molecules, and for wider studies investigating GBA2 biology.

Prisoners at ultra-high-risk for psychosis: a cross-sectional study.

BACKGROUND: The definition of ultra-high risk (UHR) for psychosis was derived from community-based help-seeking populations. Prisoners have high rates of psychosis and other severe mental health (MH) problems. They also have high rates of risk factors for psychiatric morbidity and yet they are among the populations who are less likely to seek help in the community. Despite a policy of equivalence of care for individuals in prison there are no early intervention services for psychosis in prisons in the UK. This was a study exploring feasibility of introducing such a service into a local London prison. This paper discusses the differences in MH profile of prisoners who met criteria for at-risk mental state compared with those who did not. METHOD: A two-stage procedure was used. Participants in a local London prison were routinely screened in the first week of arrival in prison with the Prodrome Questionnaire - Brief Version (PQ-B; Loewy et al. 2011). Those that screened positive as well as a small sample of those who screened negative underwent a further semi-structured assessment to see whether they met criteria for UHR state. Data on self-harm and suicide attempt, family psychiatric history, and anxiety and depression was also collected. RESULTS: A total of 891 prisoners were screened, 44% of whom screened positive. A total of 354 underwent second stage assessment, 60 of whom had screened negative. Four groups were identified: those that had no MH problems, a group experiencing First Episode Psychosis, those at UHR of psychosis and a group with other MH problems. The UHR state and Psychotic groups had very similar MH profiles of symptoms and distress. Prisoners with no MH problems were at the other end of the spectrum with few symptoms and little distress. The Other group fell in between this group and the psychotic spectrum group in terms of symptomology and distress. CONCLUSIONS: This study is the first to examine risk for psychosis in an adult male prison population. We identified a broad spectrum of MH disorder for which there is little current service provision in prisons. Screening early in the custodial process has the potential to identify unmet MH need and has implications for keeping individuals safe in custody. A long-term strategic approach is required to address MH need in prisons.

Characteristics of prisoners with neurodevelopmental disorders and difficulties.

BACKGROUND: Previous studies have found high rates of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID) within the criminal justice system (CJS). However, little is understood about prisoners with neurodevelopmental disorders and difficulties (NDD) or their needs. This study aimed to identify prisoners with NDD and compare their characteristics with prisoners without NDD on a range of socio-demographic and social functioning measures. METHOD: This was a descriptive, cross-sectional study carried out using face-to-face interviews with 240 participants in a London Category C prison. Standardised tools were used to assess prisoners for ADHD, ASD and ID. RESULTS: The study identified 87 prisoners who screened positive for one or more type of NDD. Participants with NDD were significantly younger and more likely to be single [(odds ratio) OR = 2.1], homeless (OR = 3.4) or unemployed (OR = 2.6) before they came into prison. They also had poorer educational achievements that those without NDD. Over 80% of those with NDD had a previous conviction or imprisonment. CONCLUSIONS: The findings confirm the presence of significant numbers of people with NDD in a male prison. Services across the CJS are required for this group; specifically, there is a need for raised awareness among those working in the CJS to improve the recognition of offenders with NDD. Services in the community need to work with individuals with NDD who are at risk of offending, targeting those who are homeless, unemployed and have poor employment opportunities.

Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease.

Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98-HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5)-methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds.

Intermittent pneumatic compression. A comparison of femoral vein velocity with five different devices.

AIM: Different mechanical devices for thromboprophylaxis have different flow characteristics. A new device (Vadoplex) has been developed to provide a short impulse around the calf, a concept derived from the efficacy of foot impulse technology. New devices should be compared with existing devices to establish whether it has a comparable ability to augment venous velocity. Objectives of the study were to compare the venous velocity induced by the Vadoplex with established intermittent pneumatic calf and leg compressors (Covidien and Huntleigh). METHODS: The venous velocity was established in ten healthy volunteers with standardised Duplex ultraonography of the common femoral vein. Measurements were taken at rest and on standing, with each device inactive and active. RESULTS: The Vadoplex induced an increased femoral venous velocity at least as enhanced as established calf and full leg sleeves. CONCLUSION: Calf impulse technology is an alternative to other systems in enhancing femoral vein blood flow, itself a surrogate for assumed thromboprophylactic effect.

Investigations regarding the utility of prodigiosenes to treat leukemia.

Prodigiosenes, possessing a 4-methoxypyrrolyldipyrrin skeleton, are known for their anti-cancer activity. Structural modification of the C-ring resulted in a series of prodigiosenes that displayed promising activity against leukemia cell lines during in vitro analysis against the NCI 60 cancer cell line panel. Further in vivo studies of these compounds using the zebrafish model showed persistence of anti-leukemia properties in human K562 chronic myelogenous leukemia cells.

Myelopoiesis and myeloid leukaemogenesis in the zebrafish.

Over the past ten years, studies using the zebrafish model have contributed to our understanding of vertebrate haematopoiesis, myelopoiesis, and myeloid leukaemogenesis. Novel insights into the conservation of haematopoietic lineages and improvements in our capacity to identify, isolate, and culture such haematopoietic cells continue to enhance our ability to use this simple organism to address disease biology. Coupled with the strengths of the zebrafish embryo to dissect developmental myelopoiesis and the continually expanding repertoire of models of myeloid malignancies, this versatile organism has established its niche as a valuable tool to address key questions in the field of myelopoiesis and myeloid leukaemogenesis. In this paper, we address the recent advances and future directions in the field of myelopoiesis and leukaemogenesis using the zebrafish system.

Continuity of care for recently released prisoners with mental illness: a pilot randomised controlled trial testing the feasibility of a Critical Time Intervention.

AIMS: Prisoners with mental illness on release from prison often face complex challenges with little support, leading to poor clinical and social outcomes. This feasibility study aimed to see whether a Critical Time Intervention (CTI) in the first weeks post-release effectively connects mentally ill prisoners with social, clinical, housing, and welfare services on leaving prison. The study took place in 2007 and involved local prisons in London and Manchester. METHODS: A pilot randomised controlled trial in which CTI was compared to Treatment as Usual (TAU). RESULTS: Sixty prisoners were randomised in the trial, with outcome measures completed on 23. A higher proportion of prisoners in CTI group were in contact with services at follow-up than those receiving TAU. CTI prisoners were significantly more likely to be receiving medication, and be registered with a General Practitioner (GP) than those in the TAU group. CONCLUSIONS: Continuity of care for prisoners with severe mental illness can be improved by working with them to identify their needs prior to release, and by assisting them to engage effectively to the necessary agencies in the community.

NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis.

NUP98-HOXA9 [t(7;11) (p15;p15)] is associated with inferior prognosis in de novo and treatment-related acute myeloid leukaemia (AML) and contributes to blast crisis in chronic myeloid leukaemia (CML). We have engineered an inducible transgenic zebrafish harbouring human NUP98-HOXA9 under the zebrafish spi1(pu.1) promoter. NUP98-HOXA9 perturbed zebrafish embryonic haematopoiesis, with upregulated spi1 expression at the expense of gata1a. Markers associated with more differentiated myeloid cells, lcp1, lyz, and mpx were also elevated, but to a lesser extent than spi1, suggesting differentiation of early myeloid progenitors may be impaired by NUP98-HOXA9. Following irradiation, NUP98-HOXA9-expressing embryos showed increased numbers of cells in G2-M transition compared to controls and absence of a normal apoptotic response, which may result from an upregulation of bcl2. These data suggest NUP98-HOXA9-induced oncogenesis may result from a combination of defects in haematopoiesis and an aberrant response to DNA damage. Importantly, 23% of adult NUP98-HOXA9-transgenic fish developed a myeloproliferative neoplasm (MPN) at 19-23 months of age. In summary, we have identified an embryonic haematopoietic phenotype in a transgenic zebrafish line that subsequently develops MPN. This tool provides a unique opportunity for high-throughput in vivo chemical modifier screens to identify novel therapeutic agents in high risk AML.

The Hox cofactors Meis1 and Pbx act upstream of gata1 to regulate primitive hematopoiesis.

During vertebrate development, the initial wave of hematopoiesis produces cells that help to shape the developing circulatory system and oxygenate the early embryo. The differentiation of primitive erythroid and myeloid cells occurs within a short transitory period, and is subject to precise molecular regulation by a hierarchical cascade of transcription factors. The TALE-class homeodomain transcription factors Meis and Pbx function to regulate embryonic hematopoiesis, but it is not known where Meis and Pbx proteins participate in the hematopoietic transcription factor cascade. To address these questions, we have ablated Meis1 and Pbx proteins in zebrafish, and characterized their molecular effects on known markers of primitive hematopoiesis. Embryos lacking Meis1 and Pbx exhibit a severe reduction in the expression of gata1, the earliest marker of erythroid cell fate, and fail to produce visible circulating blood cells. Concomitant with a loss of gata1, Meis1- and Pbx-depleted embryos exhibit downregulated embryonic hemoglobin (hbae3) expression, and possess increased numbers of pu.1-positive myeloid cells. gata1-overexpression rescues hbae3 expression in Pbx-depleted; meis1-morphant embryos, placing Pbx and Meis1 upstream of gata1 in the erythropoietic transcription factor hierarchy. Our study conclusively demonstrates that Meis1 and Pbx act to specify the erythropoietic cell lineage and inhibit myelopoiesis.

Pacemaker therapy for early and late sinus node dysfunction in orthotopic heart transplant recipients: a single-center experience.

BACKGROUND: Sinus node dysfunction (SND) is a well-known early complication of orthotopic heart transplantation (OHT). Its incidence over the lifetime of transplant recipients is less well characterized. The goal of this study was to determine the incidence and timing of SND treated with a permanent pacemaker in a large cohort of OHT recipients. METHODS: The databases of the Yale University Heart Transplant and Electrophysiology Services were reviewed and cross referenced. Patients who received pacemakers for SND were identified for analysis. A total of 241 patients underwent OHT using biatrial anastamoses from 1984 to 2006. Two hundred sixteen patients, 149 men and 55 women, mean age 50.2 +/- 11.6 years, survived > 5 days post-OHT. These, minus 12 lost to follow-up, were included in the analysis. RESULTS: These 204 patients were followed in the Yale Heart Transplant Clinic and had yearly electrocardiograms and 24-hour ambulatory monitoring. Of these patients, 24 (four female, 20 male, mean age at transplant 49 +/- 12 years) were felt to have clinically significant SND and received a pacemaker. Fourteen patients received pacemakers within 30 days of OHT; 10 patients received pacemakers 45 to 4,329 days after OHT. CONCLUSIONS: Although frequently seen as an early complication of OHT, SND remains a risk throughout the lifetime of OHT recipients. Its mechanism is likely multifactorial, and whether this risk can be mitigated over the long term by newer techniques such as bicaval anastamoses remains to be established.