CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.

Aortic barorecptor function was studied in spontaneously hypertensive rats (SHR) of various ages and normotensive Wistar rats. The aortic arch was isolated and perfused, and the activity of the left aortic nerve was recorded. The threshold pressure to elicit barerecptor firing was 80-120 mmHg in normotensive Wistar rats. Resetting of barorecptors (threshold pressure 160-180 mmHg) was found in all untreated SHR of 35-70 wk of age. Resetting of barorecptors was prevented in SHR by starting treatment with antihypertensive agents at the age of 11 wk. Treatment of 32-wk old SHR with antihypertensive agents for 4-6 wk resulted in reversal of barorecptor resetting in 50% animals. The percentage of SHR showing complete reversal of resetting did not increase even when the duration of treatment was tripled. In 52- to 64-wk old SHR, treated with antihypertensive agents, reversal of baroceptor resetting was seen in only 30% animals. It was concluded that baroceptor resetting in SHR was secondary to hypertension. Hypertension, in turn, induced hypertrophy of the tunica media of the aorta. Histological studies showed a close correlation between aortic hypertrophy resetting. Aortic hypertrophy may, therefore, be one of the important factors involved in baroceptor resetting.

Abstract. A criterion is given for an immersed horizontal π 1 -injective surface in a graph manifold to be separable. Examples are constructed of such surfaces, which are not separable and do not satisfy the k-plane property, for any k. It is shown that the simple loop conjecture holds in graph manifolds and that any graph manifold with boundary has an immersed horizontal surface.Mathematics Subject Classification (1991). 57N10, 57M10.

Antiangiogenesis is an appealing anticancer approach but requires continued presence of the antiangiogenic agents, which can be remedied by gene therapy. Baculovirus is an emerging gene delivery vector but only mediates transient expression (o7 days); thus, this study primarily aimed to develop a hybrid baculovirus for sustained antiangiogenic gene expression and cancer therapy. We first constructed plasmids featuring adeno-associated virus inverted terminal repeats (AAV ITRs), oriP/ Epstein-Barr virus-expressed nuclear antigen 1 (EBNA1) or Sleeping Beauty (SB) transposon and compared their efficacies in terms of persistent expression. In human embryonic kidney (HEK293) cells, AAV ITR failed to prolong the expression while oriP/EBNA1 moderately extended the expression to 35 days. In contrast, the SB system led to stable expression beyond 77 days even without antibiotic selection. Given this finding, we constructed a hybrid SB baculovirus expressing the SB transposase and harboring the transgene cassette flanked by inverted repeat/direct-repeat (IR/DR) elements recognizable by SB. The hybrid SB baculovirus efficiently transduced mammalian cells and mediated an expression duration longer than that by conventional baculoviruses, thanks to the transgene persistence and integration. The SB baculovirus (Bac-SB-T2hEA/w) expressing the antiangiogenic fusion protein comprising endostatin and angiostatin (hEA) also enabled prolonged hEA expression. With sustained hEA expression, Bac-SB-T2hEA/w repressed the angiogenesis in vivo, hindered the growth of two different tumors (prostate tumor allografts and human ovarian tumor xenografts) in mice and extended the life span of animals. These data altogether implicated the potential of the hybrid SB-baculovirus vector for prolonged hEA expression and for the treatment of multiple types of angiogenesis-dependent tumors.

SummarySelective internal radiation therapy (SIRT) with 90 yttrium microspheres is a relatively new clinical modality for treating non-resectable malignant liver tumours. This interventional radiology technique employs percutaneous microcatheterisation of the hepatic arterial vasculature to selectively deliver radioembolic microspheres into neoplastic tissue. SIRT results in measurable tumour responses or delayed disease progression in the majority of eligible patients with hepatocellular carcinoma or hepatic metastases arising from colorectal cancer. It has also been successfully used as palliative therapy for non-colorectal malignancies metastatic to the liver. Although most adverse events are mild and transient, SIRT also carries some risks for serious andrarely -fatal outcomes. In particular, entry of microspheres into non-target vessels may result in radiation-induced tissue damage, such as severe gastric ulceration or radiation cholecystitis. Radiation-induced liver disease poses another significant risk. By careful case selection, considered dose calculation and meticulous angiographic technique, it is possible to minimise the incidence of such complications to less than 10% of all treatments. As the number of physicians employing SIRT expands, there is an increasing need to consolidate clinical experience and expertise to optimise patient outcomes. Authored by a panel of clinicians experienced in treating liver tumours via SIRT, this paper collates experience in vessel mapping, embolisation, dosimetry, microsphere delivery and minimisation of non-target delivery. In addition to these clinical recommendations, the authors propose institutional criteria for introducing SIRT at new centres and for incorporating the technique into multidisciplinary care plans for patients with hepatic neoplasms.

The APS Journal Legacy Content is the corpus of 100 years of historical scientific research from the American Physiological Society research journals. This package goes back to the first issue of each of the APS journals including the American Journal of Physiology, first published in 1898. The full text scanned images of the printed pages are easily searchable. Downloads quickly in PDF format.

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