Update on the Clinical Approach to Spatial Neglect.

PURPOSE OF REVIEW: Spatial neglect is asymmetric orienting and action after a brain lesion, causing functional disability. It is common after a stroke; however, it is vastly underdocumented and undertreated. This article addresses the implementation gap in identifying and treating spatial neglect, to reduce disability and improve healthcare costs and burden. RECENT FINDINGS: Professional organizations published recommendations to implement spatial neglect care. Physicians can lead an interdisciplinary team: functionally relevant spatial neglect assessment, evidence-based spatial retraining, and integrated spatial and vision interventions can optimize outcomes. Research also strongly suggests spatial neglect adversely affects motor systems. Spatial neglect therapy might thus "kick-start" rehabilitation and improve paralysis recovery. Clinicians can implement new techniques to detect spatial neglect and lead interdisciplinary teams to promote better, integrated spatial neglect care. Future studies of brain imaging biomarkers to detect spatial neglect, and real-world applicability of prism adaptation treatment, are needed.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

Technical pre-analytical effects on the clinical biochemistry of Atlantic salmon (Salmo salar L.).

Clinical biochemistry has long been utilized in human and veterinary medicine as a vital diagnostic tool, but despite occasional studies showing its usefulness in monitoring health status in Atlantic salmon (Salmo salar L.), it has not yet been widely utilized within the aquaculture industry. This is due, in part, to a lack of an agreed protocol for collection and processing of blood prior to analysis. Moreover, while the analytical phase of clinical biochemistry is well controlled, there is a growing understanding that technical pre-analytical variables can influence analyte concentrations or activities. In addition, post-analytical interpretation of treatment effects is variable in the literature, thus making the true effect of sample treatment hard to evaluate. Therefore, a number of pre-analytical treatments have been investigated to examine their effect on analyte concentrations and activities. In addition, reference ranges for salmon plasma biochemical analytes have been established to inform veterinary practitioners and the aquaculture industry of the importance of clinical biochemistry in health and disease monitoring. Furthermore, a standardized protocol for blood collection has been proposed.

Communication Assessment and Intervention: Implications for Pediatric Hearing Loss.

Historically, children with hearing loss have fallen well behind their hearing peers in the areas of speech and language development, which has often limited their participation in a range of social, educational, and vocational activities. However, with early identification and appropriate intervention coupled with current hearing technology, children with hearing loss can achieve speech and language milestones at rates commensurate with hearing peers. To attain the best outcomes for these children, an early intervention system that provides thorough and unbiased information to families and allows for the efficient and coordinated efforts of qualified professionals must be present.

Federal privacy regulations and the provision of Early Hearing Detection and Intervention programs.

To be successful, Early Hearing Detection and Intervention (EHDI) programs require individually identifiable information about children to be shared among people who are responsible for screening, diagnosis, early intervention, family support, and medical home services. Pediatricians and other stakeholders in the EHDI process often point to federal laws that were passed to ensure privacy and confidentiality in health care and educational programs as major obstacles to achieving efficient and effective EHDI programs. In this article we summarize the provisions of 3 federal laws (the Health Insurance Portability and Accountability Act [HIPAA], the Family Education Rights and Privacy Act [FERPA], and Part C privacy regulations of the Individuals With Disabilities Education Act [IDEA]) that most directly affect information-sharing in EHDI programs. We suggest strategies for sharing the information needed to operate successful EHDI programs while remaining in compliance with these laws, including obtaining signed parental consent to share information between providers, including an option on the individual family services plan for parents to permit sharing of the plan with pediatricians and other providers, and giving copies of all relevant test results to parents to share with providers as they wish.

Cross-species amplification of primers developed from Plantago major and P. intermedia in two Hawaiian Plantago species from the section Plantago.

Thirty-nine primers, developed from the sister species Plantago major and P. intermedia, were tested in two Hawaiian Plantago species from the section Plantago. Eight primers were polymorphic, of which three were published earlier, and five are new ones presented here. Amplification and polymorphism levels appeared to be high in these Hawaiian species. These markers will be valuable for further mating system and evolutionary studies in species from the section Plantago that are closely related to P. major and P. intermedia.

Does Litomosoides sigmodontis synthesize dimethylethanolamine from choline?

Juvenile female Litomosoides sigmodontis secrete a protein (Juv-p120) highly modified with dimethylethanolamine (DMAE). In an attempt to establish the source of this decoration worms were pulsed with [3H]-choline and [3H]-ethanolamine and the radio-isotope labelled products analysed. Both isotope labels were successfully taken up by the worms, as demonstrated by labelling of phospholipids with [3H]-choline, being predominantly incorporated into phosphatidylcholine and [3H]-ethanolamine into phosphatidylethanolamine. Isotope labelling of phosphatidylethanolamine was particularly striking with the worms taking up approximately 30 times as much labelled ethanolamine as choline. It was possible to detect faint labelling of Juv-p120 with [3H]-ethanolamine after prolonged exposure periods but, unlike the situation with the phospholipids, it was much more readily labelled with [3H]-choline. When pulsing with [3H]-ethanolamine it was also possible to detect isotope-labelled phosphatidylcholine, which may ultimately account for the low levels of labelling of Juv-p120. Overall our results raise the previously unconsidered but intriguing possibility that in L. sigmodontis, choline may be the precursor of DMAE.

The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis.

OBJECTIVE: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated that ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein that is secreted by filarial nematodes, can exert anti-inflammatory action in the murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue cultures. As a first step to developing ES-62-based drugs, the aim of this study was to determine whether the PC-moiety of ES-62 was responsible for its anti-inflammatory actions. METHODS: We compared the anti-inflammatory activity of a PC-free form of recombinant ES-62 (rES-62) and a synthetic PC-ovalbumin conjugate (OVA-PC) with that of native ES-62 in the CIA model and synovial tissues from patients with rheumatoid arthritis. RESULTS: The anti-inflammatory actions of ES-62 in CIA appear to be dependent on the PC moiety as indicated by the reduction in severity of disease and also suppression of collagen-specific T helper 1 cytokine production observed when testing OVA-PC, but not rES-62. Interestingly, the anti-inflammatory activity of PC did not correlate with a reduction in anti-collagen IgG2a levels. Also, the ES-62-mediated suppression of interferon-gamma from human patient tissues could be mimicked by OVA-PC but not rES-62 or ovalbumin. CONCLUSIONS: In countries where filariasis is endemic the reduced detection of inflammatory diseases, such as rheumatoid arthritis may be because of the anti-inflammatory action of the PC moieties of ES-62. PC may thus provide the starting point for the development of novel, safe immunomodulatory therapies.

Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells.

Modulation of macrophage/dendritic cell (DC) cytokine production by the filarial nematode phosphorylcholine (PC)-containing product, ES-62, is mediated by Toll-like receptor (TLR) 4 and signal transduction depends on the TLR adaptor MyD88. Intriguingly, comparison of TLR4 knock-out (ko) mice with TLR4 mutant C3H/HeJ mice indicates that ES-62 cytokine responses are not dependent on the Pro712 residue of TLR4, which is crucial for the response to bacterial lipopolysaccharide (LPS). Because other immunomodulatory effects of ES-62 have been attributed to PC we have now investigated, using PC conjugated to ovalbumin (PC-Ova), whether PC is responsible for the interaction of ES-62 with TLR4. PC-Ova mimicked the modulation of interleukin (IL)-12 production by ES-62 in a TLR4- and MyD88-dependent manner and as with native ES-62, PC-Ova effects were not dependent on Pro712. Furthermore, both native ES-62 and PC-Ova suppressed Akt phosphorylation, whereas neither altered the activation of p38 or Erk MAP kinases. To rule out any role for the ES-62 protein component, we tested a PC-free recombinant ES-62 (rES-62) generated in the yeast Pichia pastoris. Surprisingly, rES-62 also modulated IL-12 production, but in a TLR4/MyD88-independent manner. Furthermore, rES-62 strongly activated both the p38 and Erk MAP kinases and Akt. However, recent biophysical analysis suggests there are differences in folding/shape between native and rES-62 and hence data obtained with the latter should be treated with caution. Nevertheless, although our study indicates that PC is likely to be primarily responsible for the modulation of cytokine production observed with native ES-62, an immunomodulatory role for the protein component cannot be ruled out.

Investigation of strategies with potential for producing a phosphorylcholine-free version of the filarial nematode immunomodulator, ES-62.

Phosphorylcholine (PC) is found attached to N-type glycans of proteins secreted by filarial nematodes, where it appears to act as an immunomodulator. Based on information on the structure and biosynthesis of the PC-glycan of a major secreted protein, ES-62, strategies were designed with potential for preparing PC-free material to better understand the importance of PC in filarial nematode immunomodulation. The strategies involve either enzymatic removal of PC or inhibition of its attachment during ES-62 synthesis. No method tested was found to be 100% effective although approximately 70% removal was obtained by culturing worms in Et18OCH3. Reasons for failure to obtain complete absence of PC moieties are discussed in relation to the structure and synthesis of PC-glycans and in addition PC-glycan biosynthesis is briefly commented on as a target for chemotherapy.

Lack of immunological cross-reactivity between parasite-derived and recombinant forms of ES-62, a secreted protein of Acanthocheilonema viteae.

The longevity of filarial nematodes is dependent on secreted immunomodulatory products. Previous investigation of one such product, ES-62, has suggested a critical role for post-translationally attached phosphorylcholine (PC) moieties. In order to further investigate this, ES-62 lacking PC was produced, using the Pichia pastoris recombinant gene expression system. Unlike parasite-derived ES-62, which is tetrameric the recombinant material was found to consist of a mixture of apparently stable tetramers, dimers and monomers. Nevertheless, the recombinant protein was considered to be an adequate PC-free ES-62 as it was recognized by existing antisera against the parasite-derived protein. However, subsequent to this, recognition of parasite-derived ES-62 by antibodies produced against the recombinant protein was found to be absent. In an attempt to explain this, recombinant ES-62 was subjected to structural analysis and was found to (i) contain 3 changes in amino acid composition; (ii) demonstrate significant alterations in glycosylation; (iii) show major differences in protein secondary structure. The effects of these alterations in relation to the observed change in immunogenicity were investigated and are discussed. The data presented clearly show that recognition by existing antibodies is insufficient proof that recombinant proteins can be used to mimic parasite-derived material in studies on nematode immunology and vaccination.

ES-62 is unable to modulate Toxoplasma gondii-driven Th1 responses and pathology.

ES-62, a filarial nematode-derived anti-inflammatory immunomodulator, was administered to mice in an attempt to prevent pathology associated with Toxoplasma gondii infection. The nematode product was shown to elevate mitogen and T. gondii-specific IL-10 production but was unable to inhibit Th1 responses. Consequently ES-62 could not prevent Th1 generated immunopathology.

Stage-specific and species-specific differences in the production of the mRNA and protein for the filarial nematode secreted product, ES-62.

Previous studies have shown that the secreted phosphorylcholine-containing glycoprotein of filarial nematodes, ES-62, is only present in the post-infective life-cycle stages, but that the mRNA is transcribed throughout the worm's life-cycle. The aim of this current study was to investigate whether the presence or absence of protein expression simply reflects differences in mRNA abundance. To this end, we investigated the relative abundance of ES-62 using TaqMan real time RT-PCR, in different life-cycle stages of 2 model filarial nematode parasites, Acanthocheilonema viteae and Brugia pahangi. For B. pahangi, microfilariae, infective larvae and adult worms were each found to have approximately similar levels of ES-62 mRNA. However, the corresponding stages of A. viteae differed greatly from each other with a pattern of increased mRNA production with maturation. As a rule A. viteae had higher levels of ES-62 mRNA than B. pahangi, and this was particularly noticeable in the adult stage where the difference was approximately 3500-fold higher. However, this significant difference in mRNA abundance was not reflected in the quantity of ES-62 protein secreted by the adult worms of each species, as A. viteae only secreted approximately 3 times as much ES-62 as B. pahangi. Thus, overall, the results obtained from this study indicate that ES-62 protein production does not solely reflect mRNA levels, and also suggest that the 2 nematodes may employ different mechanisms for regulating protein production.

Structure and synthesis of nematode phosphorylcholine-containing glycoconjugates.

Infection with filarial nematodes produces a chronic, long-lasting illness with adult worms able to survive within human hosts for up to 15 years. A contributor to the longevity of these parasites is the presence of phosphorylcholine (PC) on components of the worms' molecular secretions (ES). PC on ES modulates host immune responses towards an anti-inflammatory phenotype thereby generating an environment favourable for parasite survival. PC is attached to nematode ES via a covalent association with carbohydrate, which, although well-documented in bacteria and fungi, is absent from humans, making it an ideal target for the development of novel drugs. In order to produce such drugs it is first necessary to understand the structure and synthesis of nematode PC-glycans. ES-62 is the major PC-ES-product of Acanthocheilonema viteae and is a homologue of PC-ES found in human filarial nematodes. We have studied the structure and biosynthesis of PC-glycans of ES-62 by a combination of pulse-chase experiments, experiments involving the use of inhibitors of each of intracellular trafficking, oligosaccharide processing and phospholipid biosynthesis and various forms of mass spectrometry. Our indications indicate that PC is transferred in the lumen of the medial Golgi to an N-type glycan consisting of a trimannosyl core with or without core fucosylation bearing between 1 and 4 N-acetyl glucosamine residues. The structure of the PC-N-glycans found in ES-62 appears to be conserved amongst filarial nematodes in that it has additionally been identified in Onchocerca volvulus and O. gibsoni. Also, similar structures have been found in non-filarial parasitic nematodes and in the free-living nematode Caenorhabditis elegans. Finally, PC has also been recently found attached to the carbohydrate moieties of nematode glycosphingolipids and the structure of these will also be considered.

General practitioner contacts with patients before and after deliberate self harm.

BACKGROUND: Deliberate self harm (DSH) is an increasingly common problem. Although much attention is focused on suicide prevention by psychiatric services, the role of the general practitioner (GP) in the prevention of suicidal behaviour and in the aftercare of DSH patients is also important. AIM: To examine the nature and timing of GP contacts with DSH patients before and after an episode of DSH, and patients' satisfaction with these contacts. DESIGN OF STUDY: Structured interviews with patients shortly after an episode of DSH and again approximately one year later. SETTING: A representative sample of 139 DSH patients presenting to a district general hospital. METHOD: Patients were interviewed shortly after DSH and at follow-up about GP contacts, prescribed medication and psychiatric symptoms. RESULTS: At the time of DSH, 91.4% of patients were diagnosed with a psychiatric disorder (depression 69.8%), with 28% receiving treatment from psychiatric services. Two-thirds of patients had been in contact with their GP in the month before DSH, but only 13.3% reported expressing suicidal thoughts. Patients consulted their GP in the week following DSH in 40.6% of cases. Over half (57.9%) the patients discussed the reasons for their DSH at the first consultation and 69.5% reported that this was helpful. Overall, 64.3% of patients were satisfied with the follow-up consultations. CONCLUSIONS: The major role of the GP in the prevention of suicidal behaviour is in the detection and treatment of depression, and in the aftercare of DSH patients.

Deliberate self-harm is associated with allelic variation in the tryptophan hydroxylase gene (TPH A779C), but not with polymorphisms in five other serotonergic genes.

BACKGROUND: There is a heritable component to suicidal behaviour, encouraging the search for the associated risk alleles. Given the putative role of the 5-HT (5-hydroxytryptamine; serotonin) system in suicidal behaviour, serotonergic genes are leading candidates. In particular, several studies have reported an association with variants in the tryptophan hydroxylase (TPH) gene. METHOD: We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects. The polymorphisms were TPH (A779C), 5-HT transporter (5-HTT, LPR S/L), monoamine oxidase A (MAOA G941T), 5-HT1B receptor (HTR1B G861C), 5-HT2A receptor (HTR2A T102C), and 5-HT2C receptor (HTR2C Cys23Ser). Genotyping was done using polymerase chain reaction (PCR)-based assays. The primary analyses compared allele and genotype frequencies between cases and controls. There were a limited number of planned secondary analyses within the deliberate self-harm group. RESULTS: The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1.38, 95% CI 1.02-1.88; P = 0.03). None of the other polymorphisms was associated with deliberate self-harm. Within the deliberate self-harm group there were no associations with impulsivity, suicide risk, lifetime history of depression, or family history of deliberate self-harm. CONCLUSIONS: Our data extend the evidence that allelic variation in the TPH gene is a risk factor for deliberate self-harm. No evidence was found to implicate the other polymorphisms.

Identification of visual pallial telencephalon in the goldfish, Carassius auratus: a combined cytochrome oxidase and electrophysiological study.

A strategy based upon a comparative decrease in bilateral symmetry of cytochrome oxidase (COX) histochemistry following unilateral eye enucleation was used to identify the primary visual area in the area dorsalis of the telencephalon of the goldfish, Carassius auratus. The lateral zone of area dorsalis (Dl) at about the level of the anterior commissure exhibits such a bilateral difference. A parallel decline in the symmetry COX reactivity was observed in the associated part of the central zone (Dc). Electrophysiological activity using extracellular techniques confirmed the visually-driven activity of neurons in these areas. Lesions confirmed the loci in the lateral zone of area dorsalis, including both its dorsal and ventral parts. Single- and multi-unit recordings exhibited a variety of responses to different light stimuli. Single unit latency measures proved not to be a reliable measure of target areas. Responses habituated to stimuli repeated within 5 s and were only reliably evoked with intervals greater than several seconds.

Outcomes for psychiatric patients following first admission: relationships with voluntary and involuntary treatment and ethnicity.

Research suggests that there are ethnic differences in hospitalization outcomes for severely mentally ill patients. This study examined ethnic and sex differences in admission status, rapid readmission, and discharge placement of 487 patients on their first psychiatric admission. There were sex differences in admission status with significantly more male patients being involuntarily admitted than female patients. Ethnic differences in placement at discharge were not supported, but involuntarily admitted patients were over-represented in the less desirable outcome categories.

Suicide in young people aged 15-24: a psychological autopsy study.

BACKGROUND: The suicide rate in young people in the United Kingdom has increased over the last decade. As there is a paucity of information about the characteristics of young suicides we have undertaken a detailed investigation of suicides in people aged 15-24 years by means of the psychological autopsy approach. METHODS: The sample consisted of 27 subjects (25 males, two females) whose deaths received a verdict of suicide (N=24) or undetermined cause (N=3). Information was collected from informant interviews, coroners' inquest notes, medical records and psychiatric case notes. A sub-sample of 22 male subjects was compared with an age-matched sample of male deliberate self-harm (DSH) patients. RESULTS: Psychiatric disorders were diagnosed in 19 (70.4%) subjects. These were most commonly depressive disorders (55.5%). Very few individuals were receiving treatment for their disorders. Substance abuse disorders were uncommon but a substantial proportion of individuals had problems with alcohol or drug misuse. Personality disorders were present in 29.6% of subjects and disorders or personality trait accentuation in 55.6%. Comorbidity of psychiatric disorders was found in a third of subjects. The suicides were often the end-point of long-term difficulties extending back to childhood or early adolescence. In addition to mental disorders, relationship and legal difficulties were identified as relatively common contributory factors to the suicides. In comparison to deliberate self-harm patients, male suicides were more likely to use dangerous methods and live alone. LIMITATIONS: Several potential informants could not be interviewed and there was no general population control sample. CONCLUSIONS: The process leading to suicide in young people is often long term, with untreated depression in the context of personality and/or relationship difficulties being a common picture at the time of death. The prevention of suicide in the young clearly requires multiple strategies.