Search

Abstract Background Substantial empirical evidence has demonstrated that individuals who are socially isolated or have few positive social connections seem to age at a faster rate and have more chronic diseases. Oxytocin is a neurohypophyseal hormone hypothesized to coordinate both the causes and effects of positive social interactions, and may be involved in positive physiological adaptations such as buffering the deleterious effects of stress and promoting resilience. The proposed research will examine whether and how oxytocin influences responses to stress in humans and will consider effects in relation to those of social support. Methods/Design Experimental research will be used to determine whether exogenously administered oxytocin (intranasal) influences psychological and physiological outcomes under conditions of stress across gender and age in adulthood. Hypotheses to be tested are: 1) Oxytocin ameliorates the deleterious neuroendocrine, cardiovascular, and subjective effects of stress; 2) Oxytocin and social support have similar and additive stress-buffering effects; 3) Oxytocin effects are stronger in women versus men; and 4) Oxytocin effects are similar across a range of adult ages. Hypotheses will be tested with a placebo-controlled, double-blind study using a sample of healthy men and women recruited from the community. Participants are randomly assigned to receive either oxytocin or placebo. They undergo a social stress manipulation with and without social support (randomly assigned), and outcome measures are obtained at multiple times during the procedure. Discussion Understanding the determinants of healthy aging is a major public health priority and identifying effective measures to prevent or delay the onset of chronic diseases is an important goal. Experimental research on oxytocin, social relationships, and health in adulthood will contribute to the scientific knowledge base for maximizing active life and health expectancy. At conclusion of the study we will have solid evidence concerning the effects of oxytocin on stress response and whether it has similar effects across age and gender groups. A neurobiological understanding of resilience can inform efforts for both prevention and intervention of diseases or problems common in later life. Trial registration Clinical trial identification number is NCT01011465.

In recent decades, the susceptibility to degradation in both ambient and aqueous environments has prevented organic electronics from gaining rapid traction for sensing applications. Here we report an organic field-effect transistor sensor that overcomes this barrier using a solution-processable isoindigo-based polymer semiconductor. More importantly, these organic field-effect transistor sensors are stable in both freshwater and seawater environments over extended periods of time. The organic field-effect transistor sensors are further capable of selectively sensing heavy-metal ions in seawater. This discovery has potential for inexpensive, ink-jet printed, and large-scale environmental monitoring devices that can be deployed in areas once thought of as beyond the scope of organic materials.

The past couple of years have witnessed a remarkable burst in the development of organic field-effect transistors (OFETs), with a number of organic semiconductors surpassing the benchmark mobility of 10 cm(2)/(V s). In this perspective, we highlight some of the major milestones along the way to provide a historical view of OFET development, introduce the integrated molecular design concepts and process engineering approaches that lead to the current success, and identify the challenges ahead to make OFETs applicable in real applications.

Flexible pressure sensors are essential parts of an electronic skin to allow future biomedical prostheses and robots to naturally interact with humans and the environment. Mobile biomonitoring in long-term medical diagnostics is another attractive application for these sensors. Here we report the fabrication of flexible pressure-sensitive organic thin film transistors with a maximum sensitivity of 8.4 kPa(-1), a fast response time of <10 ms, high stability over >15,000 cycles and a low power consumption of <1 mW. The combination of a microstructured polydimethylsiloxane dielectric and the high-mobility semiconducting polyisoindigobithiophene-siloxane in a monolithic transistor design enabled us to operate the devices in the subthreshold regime, where the capacitance change upon compression of the dielectric is strongly amplified. We demonstrate that our sensors can be used for non-invasive, high fidelity, continuous radial artery pulse wave monitoring, which may lead to the use of flexible pressure sensors in mobile health monitoring and remote diagnostics in cardiovascular medicine.

We have synthesized a series of ethynylated phenazines and their bis-triazolyl cycloadducts to serve as metal ion sensors. Binding of metal ions is achieved through coordination to the phenazine nitrogen atom and the triazole ring. To allow metal sensing in aqueous solution, the triazole units are substituted with water-soluble ethylene glycol chains. These phenazine cycloadducts exhibit a selective affinity for binding silver ions. Examination of the halogenated analogues reveals a lowering of the band gap and the corresponding bathochromic shifts in the absorption and emission spectra. The electron-withdrawing properties of these halogens also result in significantly decreased metal-binding activity of the phenazine cycloadducts.

A series of functionalized diaza- and tetraazatetracenes was synthesized, either by condensation of an aromatic diamine with an ortho-quinone/diethyloxalate followed by chlorination with POCl(3) to give diazatetracenes or by palladium-catalyzed coupling of a phenylenediamine with various 2,3-dichloroquinoxalines to give tetraazatetracenes (after oxidation with MnO(2)). Representative examples included halogenated and nitrated derivatives. The optical properties of these azatetracenes were discussed with respect to their molecular structures and substitution patterns. The diazatetracenes and tetraazatetracenes formed two different groups that had significantly different electronic structures and properties. Furthermore, 1,2,3,4-tetrafluoro-6,11-bis((triisopropylsilyl)ethynyl)benzo[b]phenazine was synthesized, which is the first reported fluorinated diazatetracene. Single-crystal X-ray analysis of this compound is reported., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Large acenes, particularly pentacenes, are important in organic electronics applications such as thin-film transistors. Derivatives where CH units are substituted by sp(2) nitrogen atoms are rare but of potential interest as charge-transport materials. In this article, we show that pyrazine units embedded in tetracenes and pentacenes allow for additional electronegative substituents to induce unexpected redshifts in the optical transitions of diazaacenes. The presence of the pyrazine group is critical for this effect. The decrease in transition energy in the halogenated diazaacenes is due to a disproportionate lack of stabilization of the HOMO on halogen substitution. The effect results from the unsymmetrical distribution of the HOMO, which shows decreased orbital coefficients on the ring bearing chlorine substituents. The more strongly electron-accepting cyano group is predicted to shift the transitions of diazaacenes even further to the red. Electronegative substitution impacts the electronic properties of diazaacenes to a much greater degree than expected.

A click reaction furnishes water-soluble acenothiadiazole-based bistriazoles with red-shifted absorption and emission characteristics.

Enlarged acenothiadiazoles, which are easily prepared, display attractive optical and electrochemical properties. The annulation of thiadiazole to anthracene gives a stable material with optical properties similar to those of substituted pentacenes.

A new relative of pentacene: The dialkynylated tetraazapentacene (see figure) was prepared by a two-step synthesis from the corresponding quinone derivative. The heteroacene is an air-stable, dark-blue, crystalline material and is of great interest as a potential organic n-electron-transport material.

An infant with severe combined immunodeficiency (SCID) is described, who presented with severe anaemia and hepatosplenomegaly due to disseminated Bacillus Calmette-Guérin (BCG) infection involving the bone marrow, liver and spleen. After BMT, huge splenic enlargement occurred, presumably due to proliferation of engrafted donor lymphocytes, leading to severe hypersplenism. Peripheral blood cell consumption was resolved by splenectomy, but gradual loss of the marrow graft followed.

To investigate the hypothesis that target organ infection with human herpes virus-6 (HHV-6) exacerbates the clinical severity of GVHD, skin and rectal biopsies from 34 allogeneic bone marrow transplant (BMT) recipients and 23 comparative autologous recipients were studied. Biopsies and heparinised blood samples were obtained from all patients prior to and at regular intervals after BMT, and whenever GVHD was suspected. HHV-6 antigen was detected in cryostat sections by immunohistochemistry, and HHV-6 DNA in peripheral blood leucocytes (PBL) and biopsies by nested PCR. Twenty-eight (90%) of the 31 patients who engrafted developed clinical GVHD, which was mild in five, moderately severe in nine and severe in 14. Overall, HHV-6 DNA was detected in PBl in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy. Thus this study supports a role for HHV-6 in the initiation and/or exacerbation of GVHD, and suggests that the presence of HHV-6 DNA in the skin or rectum may be a factor in determining GVHD severity. If confirmed, these findings may have implications for the management of allogeneic BMT recipients.

Skin and rectal biopsy tissue from 34 allogeneic and 23 autologous BMT recipients was prospectively analysed for CMV using immunohistochemistry and PCR to investigate the hypothesis that target organ infection with CMV initiates and/or exacerbates GVHD. Biopsies were obtained prior to and at 3, 8 and 26 weeks after BMT and whenever GVHD was suspected. Surveillance specimens of peripheral blood leucocytes (PBL), urine and throat swabs were obtained every 2 weeks until 12 weeks after BMT, and whenever CMV was suspected. Cryostat sections were analysed immunohistochemically for CMV antigens and PBL and biopsies for CMV DNA by PCR. Of the 31 patients who engrafted, 28 (90%) developed GVHD clinically, confirmed histologically in 56 biopsies. GVHD proved clinically severe in 14 patients, 4 of whom had treatment-resistant GVHD. CMV was detected in PBL more frequently in patients with severe GVHD than in those with mild/moderate GVHD (29% vs. 7%). However, in all but one patient the onset of GVHD preceded detection of CMV. In biopsy specimens, CMV was detected in only 2 patients, 1 of whom had an exacerbation of GVHD temporally associated with CMV. Thus, despite a high incidence of GVHD in this series, with 56 episodes of GVHD in 28 patients, only 1 patient had CMV in biopsy tissue temporally associated with GVHD. This suggests that biopsy infection with CMV is not a major factor in initiating or exacerbating GVHD in this cohort. This study thus does not support a role for target organ infection with CMV in the pathogenesis of GVHD.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but serious complication of blood component therapy in patients with haematological malignancies. B-chronic lymphocytic leukaemia (B-CLL), however, has rarely been associated with TA-GVHD. We report three patients with advanced B-CLL who developed TA-GVHD. All these had been treated with fludarabine. Suppression of T cells by fludarabine may have contributed to an increased susceptibility to TA-GVHD. The use of irradiated blood products to prevent this complication should be considered for patients with advanced B-CLL treated with fludarabine or other purine analogues.

Materno-fetal GVHD is commonly a fatal condition occurring in patients with severe combined immunodeficiency (SCID). Definitive diagnosis is often difficult. We describe a patient with clinical features suggestive of materno-fetal GVHD but in whom histology was atypical. Y chromosome-specific PCR amplification analysis of DNA extracted from the skin biopsy was performed to detect chimeric evidence of infiltrating maternal T cells. This revealed strong positivity for the Y chromosome, indicating lack of maternal T cell engraftment and thus confirming a diagnosis of Omenn's syndrome, a variant of SCID in which atypical lymphocyte clones give rise to a similar picture. In contrast, Y chromosome-specific PCR analysis of skin biopsy DNA from a male patient with a rash clinically and histologically typical of materno-fetal GVHD revealed absence of the Y chromosome, indicating infiltration of maternal cells and thus confirming the diagnosis of materno-fetal GVHD. Y chromosome-specific PCR analysis is thus a useful investigation for the differentiation of materno-fetal GVHD from Omenn's syndrome in pre-BMT SCID patients presenting with unexplained rash.

Clinical and histological changes consistent with GVHD have been described in recipients of both syngeneic and autologous grafts. The mechanism of autologous GVHD is well documented. However, cases of autologous GVHD previously reported have all occurred within the first 2 months post-BMT. We report the case of an autologous BMT recipient in whom histological features consistent with GVHD emerged 7 months post-BMT, which may have implications for the long-term follow-up of autologous marrow graft recipients.

Aims: To define the immunopathological profile of transfusion associated graft versus host disease (TA-GvHD) to elucidate its pathophysiology and to determine if any features are of diagnostic value., Methods: Nine patients (age range 14-61 years) who developed histologically confirmed TA-GvHD between 1989 and 1992 were studied. Immunohistochemical analysis of frozen and formalin fixed skin biopsy tissue was performed. Sections were stained with antibodies to CD3, CD8, CD4 and HLA-DR, using a routine streptavidin-biotin technique with standard diaminobenzidine development., Results: All biopsy specimens showed aberrant positive expression of HLA-DR by epidermal keratinocytes. In four patients, all of whom died, HLA-DR was diffusely expressed throughout the epidermis; in the other five cases keratinocyte expression of HLA-DR was more focal. In all biopsy specimens T cells had infiltrated the dermis and epidermis. In all nine cases CD4+ T helper/inducer cells were the predominant T cells., Discussion: Immunohistochemical studies are of value in the diagnosis of TA-GvHD. Aberrant keratinocyte expression of HLA-DR and dermal and epidermal infiltration of CD4+ T cells are immunopathological features of TA-GvHD. Immunohistochemical analysis of skin biopsy tissue using antibodies to these markers is thus a useful investigation in pancytopenic patients presenting with unexplained rashes.

The pathogenesis of GVHD is not fully elucidated. Some groups of patients have a higher risk of developing GVHD post-BMT than others. Environmental factors may be important. Much attention has focused on the role of viruses, particularly herpes viruses, in GVHD. CMV in particular has been implicated as a pathogenic agent. Data from animal work and from observations of the frequent clinical association of CMV with GVHD have suggested a pathogenic link. Several large multi-centre seroepidemiological studies have been performed in an attempt to clarify this issue. This review discusses the data implicating herpes viruses in the pathogenesis of GVHD and considers the mechanisms by which viruses may exacerbate or initiate GVHD. Implications for the management of allogeneic BMT patients are discussed.