The five dimensions of B cell tolerance

B cell tolerance has been generally understood to be an acquired property of the immune system that governs antibody specificity in ways that avoid auto‐toxicity. As useful as this understanding has proved, it fails to fully explain the existence of auto‐reactive specificities in healthy individuals and contribution these may have to health. Mechanisms underlying B cell tolerance are considered to select a clonal repertoire that generates a collection of antibodies that do not bind self, ie tolerance operates more or less in three dimensions that largely spare autologous cells and antigens. Yet, most B lymphocytes in humans and probably in other vertebrates are auto‐reactive and absence of these auto‐reactive B cells is associated with disease. We suggest that auto‐reactivity can be embodied by extending the concept of tolerance by two further dimensions, one of time and circumstance and one that allows healthy cells to actively resist injury. In this novel concept, macromolecular recognition by the B cell receptor leading to deletion, anergy, receptor editing or B cell activation is extended by taking account of the time of development of normal immune responses (4th dimension) and the accommodation (or tolerance) of normal cells to bound antibody, activation of complement, and interaction with inflammatory cells (fifth dimension). We discuss how these dimensions contribute to understanding B cell biology in health or disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153034/1/imr12813.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153034/2/imr12813_am.pd

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Childhood tuberculosis deskguide and monitoring: An intervention to improve case management in Pakistan

Background: Childhood tuberculosis (TB) has been a neglected area in national TB control programme (NTCP) in high burden countries. The NTP Pakistan adapted the global approaches by developing and piloting its policy guideline on childhood TB in ten districts of the country. We developed an intervention package including a deskguide and a monitoring tool and tested with the ongoing childhood TB care in a district. The objective of our study was to measure effectiveness of intervention package with deskguide and monitoring tool by comparing TB case finding and treatment outcomes among districts in 2008, and performance assessment in intervention district. Method: An intervention study with cohort design within a routine TB control programme comparing case findings and treatment outcomes before and after the intervention, and in districts with and without intervention. We enrolled all children below 15 years registered at all nine public sector hospitals in three districts of Pakistan. The data was collected from hospital TB records. Results: In eight months during 2007 there were 164 childhood TB cases notified, and after intervention in 2008 a total of 194 cases were notified. In intervention district case finding doubled (110% increase) and correct treatment practice significantly increased in eight months. Successful outcomes were significantly higher in intervention district (37,100%) compared to control district A (18, 18%, p < 0.05) and control district B (41, 72%, p < 0.05). Conclusion: Childhood TB deskguide and structured monitoring was associated with improved case management and it augmented NTP policy. More development and implementation in all health services of the district are indicated.publishedVersio

Integrated modeling and validation for phase change with natural convection

Water-ice systems undergoing melting develop complex spatio-temporal interface dynamics and a non-trivial temperature field. In this contribution, we present computational aspects of a recently conducted validation study that aims at investigating the role of natural convection for cryo-interface dynamics of water-ice. We will present a fixed grid model known as the enthalpy porosity method. It is based on introducing a phase field and employs mixture theory. The resulting PDEs are solved using a finite volume discretization. The second part is devoted to experiments that have been conducted for model validation. The evolving water-ice interface is tracked based on optical images that shows both the water and the ice phase. To segment the phases, we use a binary Mumford Shah method, which yields a piece-wise constant approximation of the imaging data. Its jump set is the reconstruction of the measured phase interface. Our combined simulation and segmentation effort finally enables us to compare the modeled and measured phase interfaces continuously. We conclude with a discussion of our findings

Diagnosis of depression among adolescents – a clinical validation study of key questions and questionnaire

<p>Abstract</p> <p>Background</p> <p>The objective of the study is to improve general practitioners' diagnoses of adolescent depression. Major depression is ranked fourth in the worldwide disability impact.</p> <p>Method/Design</p> <p>Validation of 1) three key questions, 2) SCL-dep6, 3) SCL-10, 4) 9 other SCL questions and 5) WHO-5 in a clinical study among adolescents. The Composite International Diagnostic Interview (CIDI) is to be used as the gold standard interview. The project is a GP multicenter study to be conducted in both Norway and Denmark. Inclusion criteria are age (14–16) and fluency in the Norwegian and Danish language. A number of GPs will be recruited from both countries and at least 162 adolescents will be enrolled in the study from the patient lists of the GPs in each country, giving a total of at least 323 adolescent participants.</p> <p>Discussion</p> <p>The proportion of adolescents suffering from depressive disorders also seems to be increasing worldwide. Early interventions are known to reduce this illness. The earlier depression can be identified in adolescents, the greater the advantage. Therefore, we hope to find a suitable questionnaire that could be recommended for GPs.</p

Age-Related Differences in Ocular Features of a Naturalistic Free-Ranging Population of Rhesus Macaques

This is the final version. Available on open access from the Association for Research in Vision and Ophthalmology via the DOI in this recordPURPOSE: Rhesus macaques (Macaca mulatta) are the premier nonhuman primate model for studying human health and disease. We investigated if age was associated with clinically relevant ocular features in a large cohort of free-ranging rhesus macaques from Cayo Santiago, Puerto Rico. METHODS: We evaluated 120 rhesus macaques (73 males, 47 females) from 0 to 29 years old (mean ± SD: 12.6 ± 6.4) from September to December 2021. The ophthalmic evaluation included intraocular pressure (IOP) assessment, corneal pachymetry, biomicroscopy, A-scan biometry, automated refraction, and fundus photography after pupil dilation. The associations of age with the outcomes were investigated through multilevel mixed-effects models adjusted for sex and weight. RESULTS: On average, IOP, pachymetry, axial length, and automated refraction spherical equivalent were 18.37 ± 4.68 mmHg, 474.43 ± 32.21 µm, 19.49 ± 1.24 mm, and 0.30 ± 1.70 diopters (D), respectively. Age was significantly associated with pachymetry (β coefficient = -1.20; 95% confidence interval [CI], -2.27 to -0.14; P = 0.026), axial length (β coefficient = 0.03; 95% CI, 0.01 to 0.05; P = 0.002), and spherical equivalent (β coefficient = -0.12; 95% CI, -0.22 to -0.02; P = 0.015). No association was detected between age and IOP. The prevalence of cataracts in either eye was 10.83% (95% CI, 6.34-17.89) and was significantly associated with age (odds ratio [OR] = 1.20; 95% CI, 1.06-1.36; P = 0.004). Retinal drusen in either eye was observed in 15.00% (95% CI, 9.60-22.68) of animals, which was also significantly associated with age (OR = 1.14; 95% CI, 1.02-1.27; P = 0.020). CONCLUSIONS: Rhesus macaques exhibit age-related ocular associations similar to those observed in human aging, including decreased corneal thickness, increased axial length, myopic shift, and higher prevalence of cataract and retinal drusen.New Frontiers in Research FoundationNatural Sciences and Engineering Research CouncilCanada Research Chairs ProgramNational Aging InstituteBrightFocus FoundationNational Institutes of Health (NIH)University of Calgar

In Situ Photodegradation of Incorporated Polyanion Does Not Alter Prion Infectivity

Single-stranded polyanions ≥40 bases in length facilitate the formation of hamster scrapie prions in vitro, and polyanions co-localize with PrPSc aggregates in vivo [1], [2]. To test the hypothesis that intact polyanionic molecules might serve as a structural backbone essential for maintaining the infectious conformation(s) of PrPSc, we produced synthetic prions using a photocleavable, 100-base oligonucleotide (PC-oligo). In serial Protein Misfolding Cyclic Amplification (sPMCA) reactions using purified PrPC substrate, PC-oligo was incorporated into physical complexes with PrPSc molecules that were resistant to benzonase digestion. Exposure of these nuclease-resistant prion complexes to long wave ultraviolet light (315 nm) induced degradation of PC-oligo into 5 base fragments. Light-induced photolysis of incorporated PC-oligo did not alter the infectivity of in vitro-generated prions, as determined by bioassay in hamsters and brain homogenate sPMCA assays. Neuropathological analysis also revealed no significant differences in the neurotropism of prions containing intact versus degraded PC-oligo. These results show that polyanions >5 bases in length are not required for maintaining the infectious properties of in vitro-generated scrapie prions, and indicate that such properties are maintained either by short polyanion remnants, other co-purified cofactors, or by PrPSc molecules alone

The association between life events And suicide intent in self-poisoners with and without a history of deliberate self-harm: a preliminary study.

The associations between life events in the 12 months preceding an episode of self-poisoning resulting in hospital attendance (the index episode), and the suicide intent of this episode were compared in individuals for whom the index episode was their first, episode and in individuals in whom it was a recurrence of DSH. Results indicated a significant interaction between independent life events, repetition status, and gender in the prediction of suicide intent, the association between life events and intent being moderated by repetition status in women only. The results provide preliminary evidence to suggest the presence of a suicidal process in women, in which the impact of negative life events on suicide intent diminishes across episodes

Suicide attempts and related factors in patients admitted to a general hospital: a ten-year cross-sectional study (1997-2007)

[Abstract] Background: Suicide and suicide attempts represent a severe problem for public health services. The aim of this study is to determine the socio-demographic and psychopathological variables associated with suicide attempts in the population admitted to a General Hospital. Methods: An observational-descriptive study of patients admitted to the A Coruña University Hospital (Spain) during the period 1997-2007, assessed by the Consultation and Liaison Psychiatric Unit. We include n = 5,234 admissions from 4,509 patients. Among these admissions, n = 361 (6.9%) were subsequent to a suicide attempt. Admissions arising from a suicide attempt were compared with admissions occurring due to other reasons.Multivariate generalised estimating equation logistic regression models were used to examine factors associated with suicide attempts. Results: Adjusting by age, gender, educational level, cohabitation status, being employed or unemployed, the psychiatric diagnosis at the time of the interview and the information on previous suicide attempts, we found that the variables associated with the risk of a suicide attempt were: age, psychiatric diagnosis and previous suicide attempts. The risk of suicide attempts decreases with age (OR = 0.969). Psychiatric diagnosis was associated with a higher risk of suicide attempts, with the highest risk being found for Mood or Affective Disorders (OR = 7.49), followed by Personality Disorders (OR = 7.31), and Schizophrenia and Other Psychotic Disorders (OR = 5.03).The strongest single predictive factor for suicide attempts was a prior history of attempts (OR = 23.63). Conclusions: Age, psychopathological diagnosis and previous suicide attempts are determinants of suicide attempts

High caseload of childhood tuberculosis in hospitals on Java Island, Indonesia: a cross sectional study

Background Childhood tuberculosis (TB) has been neglected in the fight against TB. Despite implementation of Directly Observed Treatment Shortcourse (DOTS) program in public and private hospitals in Indonesia since 2000, the burden of childhood TB in hospitals was largely unknown. The goals of this study were to document the caseload and types of childhood TB in the 0-4 and 5-14 year age groups diagnosed in DOTS hospitals on Java Island, Indonesia. Methods Cross-sectional study of TB cases recorded in inpatient and outpatient registers of 32 hospitals. Cases were analyzed by hospital characteristics, age groups, and types of TB. The number of cases reported in the outpatient unit was compared with that recorded in the TB register. Results Of 5,877 TB cases in the inpatient unit and 15,694 in the outpatient unit, 11% (648) and 27% (4,173) respectively were children. Most of the childhood TB cases were under five years old (56% and 53% in the inpatient and outpatient clinics respectively). The proportion of smear positive TB was twice as high in the inpatient compared to the outpatient units (15.6% vs 8.1%). Extra-pulmonary TB accounted for 15% and 6% of TB cases in inpatient and outpatient clinics respectively. Among children recorded in hospitals only 1.6% were reported to the National TB Program. Conclusion In response to the high caseload and gross under-reporting of childhood TB cases, the National TB Program should give higher priority for childhood TB case management in designated DOTS hospitals. In addition, an international guidance on childhood TB recording and reporting and improved diagnostics and standardized classification is require