Recurrent pregnancy loss is an unfortunate fact of life for many women. This special issue of the Biomedical Journal includes four review articles from renowned experts discussing the factors important for a successful pregnancy and, in particular, the complex immunological dialog between mother and fetus. We also focus on an animal study investigating the utility of skin-derived hydrogels for wound healing, unearth the details of a rare stomach cancer, and discover new applications for silver in dentistry.

The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

Recurrent pregnancy loss, defined as a pregnancy failure occurring before 24 weeks of gestation more than two or three times according to most definitions, is a fertility defect encountered in 1-5% of the patients. This defect is of course of multifactorial origin. Among the possible origins of recurrent pregnancy loss are uterine structural defaults, defective ploidy control of the embryo, defective immunological dialog between the embryo (or the fetus) and the uterus sometimes in relation with immunological disorders (such as autoimmune diseases), thrombophilia, and free radical metabolism imbalance. Numerous studies attempted to correlate variants of genes supposed to be intervening in the different facets of the early maternal-fetal or maternal-embryonic dialog, and eventually modify the outcome of fertilization, leading to success or failure of post-implantation development. The objective of the present review is to portray the major genes and gene polymorphisms studied for their putative association with recurrent pregnancy loss. Most of these genes have been studied as candidate genes for which strong biological arguments were put forward as to their putative involvement in recurrent pregnancy loss. They were mostly studied by genetic analysis, often in various populations of different ethnic origins, throughout the world. Some of these studies were available only in English as abstracts and were nevertheless used if the information was given with enough detail. With the space being too short to depict all the available literature, different major pathways releva nt to the scientific question are presented without any attempt to hide the fact that discordant views often aroused for a given gene.

Tolerance of the fetus by the maternal immune system is regulated through various mechanisms involving the different immune cells, both in the periphery and locally at the feto-maternal interface. The maternal T lymphocytes are aware of the paternal fetal antigens and a state of dynamic T cell homeostasis is maintained in the uterus during gestation, which involves increase in antigen-specific regulatory T cell (Treg) proliferation, increase in apoptosis of antigen-specific effector T cells, and inhibition of excessive inflammation post successful implantation to ensure tolerance to the fetus. The Tregs play an important role in the maintenance of tolerance during gestation. Recently, the inflammatory T helper type 17 (Th17) cells are reported to have a role in loss of tolerance to the fetus. The interaction between costimulatory molecule programmed death 1 (PD1) and its ligand PDL1 is known to play a role in regulating both the Tregs and Th17 cells. Here we discuss how the PD1/PDL1 pathway affects these two T cell populations and its role in feto-maternal tolerance.

Despite a number of controversies, the functional importance of human leukocyte antigen G (HLA-G) in early human pregnancy is now sustained by a large amount of sound data. Membrane-bound and soluble HLA-G isoforms, either as β2-microglobulin-free or -associated as monomers or dimers, are expressed by different trophoblast subpopulations, the only fetal-derived cells that are directly in contact with maternal cells (maternal-fetal interfaces). Trophoblast HLA-G is the specific ligand of multiple cellular receptors present in maternal immune and non-immune cells, including CD8, leukocyte immunoglobulin-like receptor (LILR) B1, LILRB2, killer cell immunoglobulin-like receptor (KIR) 2DL4, and possibly CD160. Trophoblast HLA-G specific engagement of these cellular receptors triggers either inhibitory or activating signals in decidual CD8 ⁺ T cells, CD4 ⁺ T cells, natural killer (NK) cells, macrophages, dendritic cells, or endothelial cells. Such HLA-G-receptor specific interactions first contribute to limit potentially harmful maternal anti-paternal immune response by impairment of decidual NK cell cytotoxicity, inhibition of CD4 ⁺ and CD8 ⁺ T-cell and B-cell proliferation, and induction of apoptosis of activated CD8 ⁺ T cells. Second, these HLA-G specific interactions contribute to stimulate placental development through secretion of angiogenic factors by decidual NK cells and macrophages, and to provide a protective effect for the outcome of pregnancy by the secretion of interleukin (IL)-4 by decidual trophoblast antigen-specific CD4 ⁺ T cells.

Non-inherited maternal antigens (NIMA) are those protein products derived from polymorphic genes that the mothers express but not the offspring. During normal human pregnancy, a bidirectional regulation occurs in such a way that the maternal immune system tolerates the inherited paternal antigens (IPA) expressed by the fetus and the developing fetal immune system tolerates NIMA. The process by which the described bidirectional regulation is developed is related to microchimerism, due to the bidirectional traffic of cells allowed by the decidua-trophoblast interface. An extensive body of knowledge from the transplantation and pregnancy physiology fields suggests a role for microchimerism and NIMA exposure in the development of NIMA-specific alloresponse regulation, which may include transforming growth factor β (TGF-β) as well as interleukin (IL)-10 and IL-35, producing peripheral T regulatory lymphocytes. The induction of this NIMA-specific allotolerance is called the "NIMA effect." Some experimental data suggest the existence of a "split tolerance" phenomenon associated with NIMA effect, in which regulation of NIMA-specific indirect pathway is induced without tolerogenic impact on the direct pathway. In this review, the most relevant literature about the immunological phenomena underlying the NIMA effect is discussed, including the most recent proposals about the role played by antigen-acquisition and the semi-direct pathway of allorecognition.

Background: This study was designed to analyze the post-rehabilitation occlusal function of subjects treated with complex mandibular resection and subsequently rehabilitated with fibula osteoseptocutaneous flaps, dental implants, and fixed prostheses utilizing the T-scan system. Methods: Ten mandibular complex resection cases that adopted fibula osteoseptocutaneous flaps, dental implants, and fixed prostheses to reconstruct occlusal function were analyzed. The mandibular reconstructions were divided into three groups based on size: full mandibular reconstructions, mandibular reconstructions larger than half of the arch, and mandibular reconstructions smaller than half of the arch. The T-scan III system was used to measure maximum occlusal force, occlusal time, anterior-posterior as well as left-right occlusal force asymmetries, and anterior-posterior as well as left-right asymmetrical locations of occlusal centers. Results: Subjects with larger mandibular reconstructions and dental implants with fixed partial dentures demonstrated decreased average occlusal force; however, the difference did not reach the statistically significant level (p > 0.05). The most significant asymmetry of occlusal center location occurred among subjects with mandibular reconstructed areas larger than half of the mandibular arch. Conclusions: Comparison of the parameters of T-scan system used to analyze the occlusal function showed that the occlusal force was not an objective reference. Measurements of the location of the occlusal center appeared more repeatable, and were less affected by additional factors. The research results of this study showed that the size of a reconstruction did not affect the occlusal force after reconstruction and larger reconstructed areas did not decrease the average occlusal force. The most significant parameter was left and right asymmetry of the occlusion center (LROC) and was measured in subjects with reconstruction areas larger than half of the arch.

Background: Wound healing and skin tissue engineering are mediated, in part, by interactions between cells and the extracellular matrix (ECM). A subset of the ECM, basement membranes (BM), plays a vital role in regulating proper skin healing and function. Methods: ECM-rich, tissue-specific hydrogels were extracted and assembled from dermis samples. These hydrogels contain BM proteins vital to skin regeneration, including laminin β3, collagen IV, and collagen VII. The extracts could be assembled to form hydrogels by either temperature or pH mechanism, with the mechanical properties and structure varying with the mechanism of assembly. A wound healing model was developed to investigate the ability of these hydrogels to enhance healing with a single application in vivo. Results: The pH, but not temperature gels were easily applied to the wounds. There were no signs of increased inflammation due to the application of the hydrogels. The width of granulation tissue at the first week was reduced (p = 0.064) relative to controls with the application of hydrogel. There were no changes in wound closure rates or vessel density. Conclusions: Dermis-derived hydrogels contain BM proteins important for skin regeneration. They can be easily applied, but their poor mechanical strength and rapid degradation may hinder their biological effects.

Background: Gastric hepatoid adenocarcinoma (GHA), a rare type of primary gastric cancer, is characterized by hepatocellular carcinoma-like histology. As details of this disease remain unknown, the aim of this study was to evaluate the clinicopathological features of GHA. Methods: From January 2001 to December 2010, 4563 patients were diagnosed with primary gastric cancer at Chang Gung Memorial Hospital, Linkou Medical Center. Ten (0.22%) of these patients were diagnosed with GHA. The clinicopathological characteristics of these patients were collected retrospectively. Results: The median age at diagnosis was 65.5 years, and six patients (60%) were male. Seven patients had lymph node metastasis and five had distant metastasis, with the liver as the most common site (four cases). Serum alpha-fetoprotein (AFP) levels were elevated in seven of eight patients (median: 359.2 ng/ml; range: 4.3-6535.6 ng/ml). Endoscopically, six tumors were classified as Borrmann's type III cancer with the appearance of fungating mass lesion with a purple, berry-like surface. Of the five patients without distant metastasis, all received curative-intent surgery and four received adjuvant chemotherapy. Four patients with distant metastasis received either palliative operation or chemotherapy, and one patient received neither operation nor chemotherapy due to a poor performance status. The median survival time was 7.2 months (range: 0.7-131.8 months), and the 5-year survival rate was 20%. There was survival benefit in the chemotherapy groups. Conclusions: GHA is a rare subtype of gastric cancer which is prone to lymph node and liver metastasis. Most GHAs appear as Borrmann's type III fungating mass lesion with a purple, berry-like surface. Although the prognosis of advanced stage GHA is poor, chemotherapy might provide some benefit.

Background: Herpes viruses can be reactivated among immunocompetent patients in intensive care unit (ICU). Cytomegalovirus (CMV) and herpes simplex virus (HSV) have been the most studied. We hypothesized that Epstein-Barr virus (EBV) could also be reactivated in immunocompetent patients during their stay in ICU and that this would be associated with morbidity and mortality. Methods: This prospective observational study included 90 patients with an ICU stay of ≥ 5 days. CMV and HSV were considered when clinically suspected and DNA was researched in blood or bronchoalveolar lavage (BAL). EBV DNA viral quantification was performed in the blood samples. Results: EBV DNA was detected in blood of 61 patients (median length for positivity of 7.5 days). CMV DNA was detected in blood of 16 patients (median length for positivity of 13.5 days) and BAL of 6 patients. HSV1 DNA was detected in the BAL of 28 patients (median length for positivity of 7.5 days). Nineteen patients had no viral reactivation, 1 experienced only CMV, 32 had only EBV, 5 had only HSV, 6 had EBV and CMV, 14 had EBV and HSV, and 9 patients reactivated three viruses. Mortality was higher among patients with EBV reactivation (33/61 vs. 7/25, p = 0.02). Length of stay (21 vs. 10 days, p < 0.001) and length of mechanical ventilation (15 vs. 7 days, p < 0.001) were higher among patients with EBV reactivation. Conclusions: This study shows that EBV DNA is detected in blood of diverse ICU patients with ≥ 5 days of stay and that it is associated with morbidity and mortality. Larger dynamic prospective studies are needed to correlate viral reactivation with immune system evolution during ICU stay and to determine the role of polyviral reactivations.

Background: Nanoparticles of silver (NanoAg) have been shown to control the growth of bacteria, but application of NanoAg in endodontics has not been evaluated. This in vitro study evaluates the antimicrobial activity of NanoAg to enhance the inhibitory effects of mineral trioxide aggregate (MTA). Methods: The antibacterial activities of NanoAg and NanoAg-MTA against four types of anaerobic pathogens were tested in vitro using (1) agar diffusion test (ADT) and (2) a newly devised membrane-enclosed immersion test (MEIT). Results: Both NanoAg and NanoAg-MTA inhibited the growth of all four test bacteria at 25 ppm concentration. MEIT analysis consistently showed that NanoAg enhanced the antimicrobial activity of MTA significantly, and the bacterial susceptibility to lower concentrations of NanoAg varied depending on the type of bacteria. Overall, NanoAg-MTA showed significant inhibitory effect which was time and dose dependent. Conclusions: Our data support that NanoAg can serve as an excellent MTA additive against anaerobic endodontic-periodontal pathogens with clinical applications for infection control in endodontics.

Background: Although maximal heart rate (HR _max) is widely used to assess exercise intensity in sport training, and particularly in soccer, there are limited data with regards to the use of age-based prediction equations of HR _max in soccer players. The aim of this study was to compare the measured-HR _max with two prediction equations (Fox-HR _max = 220 – age and Tanaka-HR _max = 208 – 0.7 × age) in soccer players. Methods: Adolescent (n = 162, 15.8 ± 1.5 years) and adult players (n = 158, 23.4 ± 4.6 years), all members of competitive clubs, voluntarily performed a graded exercise field test (Conconi protocol) to assess HR _max . Results: The measured-HR _max (197.6 ± 9.4 bpm in total, 200.2 ± 7.9 bpm in adolescent players, and 195.0 ± 10.0 bpm in adult players) was explained by the formula HR _max = 212.3 – 0.75 × age (r = −0.41, standard error of the estimate = 8.6). In the total sample, Fox-HR _max overestimated measured-HR _max [mean difference (95% confidence intervals) = 2.8 bpm (1.6; 3.9)], while Tanaka-HR _max underestimated HR _max [–3.3 bpm (–4.5; –2.2)]. In adolescents, Fox-HR _max overestimated measured-HR _max [4.0 bpm (2.5; 5.5)] and Tanaka-HR _max underestimated HR _max [– 3.2 bpm (–4.7; –1.8)]. In adults, Tanaka-HR _max underestimated HR _max [–5.0 bpm (–5.3; –4.7)], while there was not any difference between Fox-HR _max and measured-HR _max [1.6 bpm (–3.4; 0.2)]. Conclusions: The results of this study failed to validate two widely used prediction equations in a large sample of soccer players, indicating the need for a sport-specific equation. On the other hand, the new equation that we presented should be investigated further by future studies before being adopted by coaches and fitness trainers.

Background: A full spectrum of medical education requires not only clinical skills but also humanistic qualities in the medical professionals, which can be facilitated by an integrated training program. An integrated project was created to improve one's medical intellectual and communication competence and to enable them to become docents who can perform well, as well as for development of their humanitarian nature. The aim of this study was to suggest an integrated program that provided approaches for creating positive effects in medical history education. Methods: Taiwan Medical Museum conducted a project on medical history lessons and docent training program; 51 participants (24 male and 27 female) attended this plan. Targets took pre-tests before lectures, attended courses of medical history, and then took post-tests. Next, they received a series of lessons on presentation skills and practiced for guiding performance. After all the training processes, the attendees succeeded in all evaluations in order to guide exhibition visitors. Data were analyzed using paired t test. Results: Two types of assessments were followed, i.e., cognitive examination and guiding practice, and both were related to good performance. Reliability (Cronbach's α) was 0.737 for the cognitive examination and 0.87 for the guiding evaluation. It indicated that the integrated program for docent training resulted in a significant difference (p ≦ 0.0001). Conclusion: The participants demonstrated better achievement and knowledge acquisition through the entire process, which led to great performance when approached by the visitors. The whole project helped to shape up a good docent and to accumulate positive learning experiences for medical professionals as well. Therefore, an integrated program is recommended to medical history education in the future.