Transplant immunology for non-immunologist

Transplantation is the treatment of choice for end-stage kidney, heart, lung, and liver disease. Short-term outcomes in solid-organ transplantation are excellent, but long-term outcomes remain suboptimal. Advances in immune suppression and human leukocyte antigen matching techniques have reduced the acute rejection rate to <10%. Chronic allograft injury remains problematic and is in part immune-mediated. This injury is orchestrated by a complex adaptive and innate immune system that has evolved to protect the organism from infection, but, in the context of transplantation, could result in allograft rejection. Such chronic injury is partially mediated by anti-human leukocyte antigen antibodies. Severe rejections have largely been avoided by the development of tissue-typing techniques and crossmatch testing, which are discussed in detail. Further advances in the understanding of T- and B-cell immunology have led to the development of new immunomodulatory therapies directed at prolonging allograft survival, including those that decrease antibody production as well as those that remove antibodies from circulation. Further application of these immunomodulatory therapies has allowed expansion of the donor pool in some cases by permitting ABO-incompatible transplantation and transplantation in patients with preformed antibodies. Although vast improvements have been made in allograft survival, patients must remain on lifetime immunosuppression. Withdrawal of immunosuppression almost always ultimately leads to allograft rejection. The ultimate dream of transplant biologists is the induction of tolerance, where immune function remains intact but the allograft is not rejected in the face of withdrawn immunosuppression. This, however, has remained a significant challenge in human studies.     

A coupled experimental and computational approach to quantify deleterious hemodynamics, vascular alterations, and mechanisms of long-term morbidity in response to aortic coarctation

IntroductionCoarctation of the aorta (CoA) is associated with morbidity despite treatment. Although mechanisms remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We present a novel approach that facilitates quantification of coarctation-induced mechanical alterations and their impact on vascular structure and function, without genetic or confounding factors.MethodsRabbits underwent thoracic CoA at 10 weeks of age (~ 9 human years) to induce a 20 mm Hg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using imaging and BP data at 32 weeks to quantify velocity, strain and wall shear stress (WSS) for comparison to vascular structure and function as revealed by histology and myograph results.ResultsSystolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular thickening, disorganization and endothelial dysfunction proximally and distally. Corrected rabbits had less severe medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12 weeks of normal BP (~ 4 human years) after the suture dissolved. WSS was elevated distally for CoA rabbits, but reduced for corrected rabbits.DiscussionThese findings are consistent with alterations in humans. We are now poised to investigate mechanical contributions to mechanisms of morbidity in CoA using these methods.     

Validation of sleep nasendoscopy for assessment of snoring with bispectral index monitoring

Bispectral index (BIS) monitor is a neurophysiological monitoring device which continually analyses a patient’s electroencephalogram during sedation and general anaesthesia to assess the level of consciousness and depth of anaesthesia. BIS monitoring, whilst performing sleep nasendoscopy (using midazolam and propofol), has helped validate depth of sedation and allowed comparison with levels of sedation of control patients during natural sleep. A prospective study of 30 patients with snoring undergoing sleep nasendoscopy with BIS monitoring was conducted. BIS monitoring was recorded throughout the procedure and assessment of snoring was made at the appropriate level of sedation and snoring. BIS values were compared with control patients. The 30 patients undergoing sleep nasendoscopy had average BIS values ranging from 50.72 to 61.2. Similar results were seen with BIS and oxygen saturation in the control group. BIS monitoring provides an adjunct to the assessment of sleep nasendoscopy in determining the level of sedation required for snoring assessment. Comparable BIS values and oxygen saturation levels were obtained between controls and patients during sedation-induced sleep, thus validating the role of sleep nasendoscopy.     

Hedgehog and Notch signaling regulate self-renewal of undifferentiated pleomorphic sarcomas

Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.     

Synthesis, antileukemic and antiplatelet activities of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines

The synthesis, antileukemic and antiplatelet activity evaluation of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines are described. In general, it was found that compound 17o showed moderate antileukemic activity against MOLT3 human leukemic cancer cell lines. An arachidonic acid induced platelet aggregation effect on washed rat platelets was studied. Compound 17i was found to be the most potent. The antiplatelet properties may be mediated by interference with the arachidonic acid pathway.     

Insights into the structural requirements of farnesyltransferase inhibitors as potential anti-tumor agents based on 3D-QSAR CoMFA and CoMSIA models

A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on three different chemical series reported as selective farnesyltransferase (FTase) inhibitors employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) techniques to investigate the structural requirements for substrates and derive a predictive model that may be used for the design of novel FTase inhibitors. Removal of outliers improved the predictive power of models developed for all three structurally diverse classes of compounds. 3D-QSAR models were derived for 3-aminopyrrolidinone derivatives (training set N=38, test set N=7), 2-amino-nicotinonitriles (training set N=46, test set N=13) and 1-aryl-1'-imidazolyl methyl ethers (training set N=35, test set N=5). The CoMFA models with steric and electrostatic fields exhibited r(2)(cv) 0.479-0.803, r(2)(ncv) 0.945-0.993, r(2)(pred) 0.686-0.811. The CoMSIA models displayed r(2)(cv) 0.411-0.814, r(2)(ncv) 0.923-0.984, r(2)(pred) 0.399-0.787. 3D contour maps generated from these models were analyzed individually, which provide the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of farnesyltransferase additionally helps in understanding the structural requirements of these inhibitors. 3D-QSAR models developed may guide our efforts in designing and predicting the FTase inhibitory activity of novel molecules.     

Improved health outcomes in urban slums through infrastructure upgrading

The world is rapidly urbanizing with over half the population now living in urban areas. As the urban population grows, so does the proportion of these persons living in slums where conditions are deplorable. These conditions concentrate health hazards leading to higher rates of morbidity and mortality. This growing problem creates a unique challenge for policymakers and public health practitioners. While the Millennium Development Goals (MDGs) aim to address these conditions and standards for water and sanitation as well as pertinent health outcomes, little evidence on interventions exists to guide policymakers. Upgrades in slum household water and sanitation systems have not yet been rigorously evaluated to demonstrate whether there is a direct link to improved health outcomes. This study aims to show that slum upgrading as carried out in Ahmedabad, India, led to a significant decline in waterborne illness incidence. We employ a quasi-experimental regression model using health insurance claims (for 2001–2008) as a proxy for passive surveillance of disease incidence. We found that slum upgrading reduced a claimant’s likelihood of claiming for waterborne illness from 32% to 14% and from 25% to 10% excluding mosquito-related illnesses. This study shows that upgrades in slum household infrastructure can lead to improved health outcomes and help achieve the MDGs. It also provides guidance on how upgrading in this context using microfinance and a public–private partnership can provide an avenue to affect positive change.