Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

T‐cell division is central to maintaining a stable T‐cell pool in adults. It also enables T‐cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T‐cell survival in lymphoreplete settings, IL‐7 and T‐cell receptor (TCR) interactions with self‐peptide MHC (pMHC), induce division when T‐cell numbers are low. The strength of reactivity for self‐pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia‐induced proliferation (LIP), in that weakly self‐reactive T cells are unable to divide, implying that T‐cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self‐reactivity and thus compromise T‐cell diversity. Here, we show that while CD4⁺ T cells with low self‐pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4⁺ T cells with low self‐pMHC reactivity are able to contribute to the reconstitution of the T‐cell pool.     

Strength and endurance training of an individual with left upper and lower limb amputations

Purpose:?The purpose of this article is to describe the development of a strength and endurance training programme designed to prepare an individual with a left glenohumeral disarticulation and transtibial amputation for a bike trip across the USA.

Method:?The subject was scheduled for training three times per week over a two-month period followed by two times per week for an additional two months. Training consisted of a resistance training circuit using variable resistance machines, cycling using a recumbent stationary bike, and core stability training using stability ball exercises. Changes in strength were assessed using 10 RM tests on the resistance machines and changes in peak VO₂ were monitored utilizing the Cosmed K4b²® pulmonary function tester.

Results:?The subject demonstrated a 30.3% gain in peak VO₂. The subject's 10 RM for left single limb leg press increased 36.8% and gains of at least 7.7% were seen for all other muscle groups tested.

Conclusion:?The strength and endurance training programme adapted to compensate for this subject's limb losses was effective in increasing both strength and peak VO₂. Adapting exercise programmes to compensate for limb loss may allow individuals with amputations to participate in physically challenging activities that otherwise may not be available to them.     

Autonomic and orthostatic dysfunction in primary Sjögren's syndrome

OBJECTIVE: Exocrine function always is and autonomic nervous function may be impaired in primary Sj?gren's syndrome (pSS). Since autonomic nervous signaling is a prerequisite for exocrine secretion we wanted to assess autonomic nervous function in pSS and relate it to diagnostic measures of exocrine function. METHODS: Autonomic nervous function was determined in 46 patients with pSS using the deep breathing test [expiration/inspiration (E/I) ratio], orthostatic test [acceleration index (AI), orthostatic systolic and diastolic blood pressure response (lSBP ratio and lDBP ratio)], and finger skin blood flow test [vasoconstrictory (VAC) score]. The results were corrected for age and expressed as z-scores by comparison with 3 control groups (E/I ratio and AI, n = 56; lSBP ratio and lDBP ratio, n = 238; and VAC score, n = 80). Exocrine gland function was determined in patients with pSS using the objective functional Schirmer-I test and rose-bengal staining (van Bijsterveld score) for the lacrimal glands and unstimulated whole sialometry for the salivary glands. RESULTS: The E/I ratio and orthostatic systolic and diastolic blood pressures were significantly decreased and the VAC score was significantly increased in patients with pSS compared to controls, indicating both parasympathetic and sympathetic dysfunction. Autonomic and exocrine function measures were found to associate poorly. CONCLUSION: Patients with pSS showed signs of both parasympathetic and sympathetic dysfunction. However, an association between cardiovascular autonomic and exocrine function in pSS was not detected.     

Coffee consumption and risk of rheumatoid arthritis

OBJECTIVE: Recent reports have suggested an association between consumption of coffee or decaffeinated coffee and the risk of rheumatoid arthritis (RA), although data are sparse and somewhat inconsistent. Furthermore, existing studies measured dietary exposures and potential confounders only at baseline and did not consider possible changes in diet or lifestyle over the followup period. We studied whether coffee, decaffeinated coffee, total coffee, tea, or overall caffeine consumption was associated with the risk of RA, using the Nurses' Health Study, a longitudinal cohort study of 121,701 women. METHODS: Information on beverage consumption was assessed with a food frequency questionnaire (FFQ) that was completed every 4 years, from baseline in 1980 through 1998. Among the 83,124 women who completed the FFQ at baseline, the diagnosis of incident RA (between 1980 and 2000) was confirmed in 480 women by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria. Relationships between intake of various beverages and the risk of RA were assessed in age-adjusted models and in multivariate Cox proportional hazards models including the cumulative average intake of each beverage during the followup period, adjusted for numerous potential confounders. In addition, for direct comparisons with prior reports, multivariate analyses were repeated using only baseline beverage information. RESULTS: We did not find a significant association between decaffeinated coffee consumption of >/=4 cups/day (compared with no decaffeinated coffee consumption) and subsequent risk of incident RA, in either an adjusted multivariate model (relative risk [RR] 1.1, 95% confidence interval [95% CI] 0.5-2.2) or a multivariate model using only baseline reports of decaffeinated coffee consumption (RR 1.0, 95% CI 0.6-1.7). Similarly, there was no relationship between cumulative caffeinated coffee consumption and RA risk (RR 1.1, 95% CI 0.8-1.6 for >/=4 cups per day versus none) or between tea consumption and RA risk (RR 1.1, 95% CI 0.7-1.8 for >3 cups/day versus none). Total coffee and total caffeine consumption were also not associated with the risk of RA. CONCLUSION: In this large, prospective study, we find little evidence of an association between coffee, decaffeinated coffee, or tea consumption and the risk of RA among women.     

Helping high-risk youth move through high-risk periods: personally controlled health records for improving social and health care transitions

Background

New patient-centered information technologies are needed to address risks associated with health care transitions for adolescents and young adults with diabetes, including systems that support individual and structural impediments to self- and clinical-care.

Methods

We describe the personally controlled health record (PCHR) system platform and its key structural capabilities and assess its alignment with tenets of the chronic care model (CCM) and the social–behavioral and health care ecologies within which adolescents and young adults with diabetes mature.

Results

Configured as Web-based platforms, PCHRs can support a new class of patient-facing applications that serve as monitoring and support systems for adolescents navigating complex social, developmental, and health care transitions. The approach can enable supportive interventions tailored to individual patient needs to boost adherence, self-management, and monitoring.

Conclusions

The PCHR platform is a paradigm shift for the organization of health information systems and is consistent with the CCM and conceptualizations of patient- and family-centered care for diabetes. Advancing the approach augers well for improvement around health care transitions for youth and also requires that we address (i) structural barriers impacting diabetes care for maturing youth; (ii) challenges around health and technology literacy; (iii) privacy and confidentiality issues, including sharing of health information within family and institutional systems; and (iv) needs for evaluation around uptake, impacts, and outcomes.     

Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-Å X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen''s efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.     

Focal white matter density changes in schizophrenia: reduced inter-hemispheric connectivity

Gray matter changes have been demonstrated in several regions in schizophrenia. Particularly, the frontal and temporal cortices and amygdala-hippocampal region have been found decreased in volume and density in magnetic resonance imaging (MRI) studies. These abnormalities may reflect an aberrant neuronal network in schizophrenia, suggesting that white matter fibers connecting these regions may also be affected. However, it is unclear if particular white matter areas are (progressively) affected in schizophrenia and if these are related to the gray matter changes.Focal white matter changes in schizophrenia were studied in whole brain magnetic resonance images acquired from 159 patients with schizophrenia or schizophreniform disorder and 158 healthy comparison subjects using voxel-based morphometry. White matter density changes in the patients with schizophrenia were correlated to gray matter density changes and to illness severity.In the patients with schizophrenia, significant decreases in white matter density were found in the genu and truncus of the corpus callosum in the left and right hemisphere, in the right anterior internal capsule and in the right anterior commissure. No interactions between diagnosis and age were found. Increased illness severity was correlated with low density of the corpus callosum and anterior commissure. Decreased corpus callosum density correlated with decreased density of thalamus, lateral inferior frontal and insular gray matter in patients and controls and with decreased density of medial orbitofrontal and superior temporal gyri in patients. Decreased internal capsule and anterior commissure density correlated with increased caudate, and globus pallidus density in patients and controls.These findings suggest aberrant inter-hemispheric connectivity of anterior cortical and sub-cortical brain regions in schizophrenia, reflecting decreased hemispheric specialisation in schizophrenia.     

Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five- year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.     

Informed consent for intravascular administration of contrast material: how much is enough?

To determine the usefulness of informed consent prior to the intravascular administration of contrast material, the authors evaluated four equal groups of patients with different degrees of counseling concerning risks and risk factors. Group 1 was given no information. Group 2 was informed of the common risks in a written statement. Group 3 was informed of all known risks in a written statement. Group 4 was informed of all known risks by means of physician counseling. The average times it took for the technologist (groups 1-3) or the physician (group 4) to counsel the patient and obtain informed consent were 1.7, 6.2, 13.6, and 11.4 minutes, respectively. Counseling by physicians would require approximately 7% of their professional time in a busy radiology department. On a postprocedure test, the patients in groups 1-4 scored on average 38.4%, 68.2%, 63.2%, and 69.8%, respectively. There was no statistical difference in the performance of groups 2-4 on the postprocedure test. If informed consent is to be obtained prior to intravascular administration of contrast material, use of a straightforward written consent form detailing the common risks and risk factors appears to be the best method.