Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome : a case report

Background: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. Case presentation: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient’s attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. Conclusions: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated

Prognostic factors for progression of visual field deterioration in patients with primary open-angle glaucoma

Regulatory T cells (Tregs) play an important role in the maintenance of self-tolerance and immune homeostasis. Interleukin-2 (IL-2) is critical for Treg expansion, activity and survival. Previous studies have demonstrated that low-dose IL-2 resulted in the selective expansion of Tregs and the clinical improvement of auto-immune disease. To examine the mechanisms whereby IL-2 affects Treg apoptosis through the intrinsic pathway, we used BH3 profiling, and quantitated mitochondrial apoptotic priming. This pattern suggests that Tregs were more primed than conventional CD4 T cells (Tcons) in a BCL2-dependent manner. Tregs expressed lower levels of BCL2 than Tcons. To examine the functional effects of IL-2, sorted Tregs and Tcons were cultured with different concentrations of IL-2. Low-dose IL-2 (10 IU/mL) lowered priming and increased BCL2 expression in Tregs. However, higher concentrations of IL-2 (>100 IU/mL) were required to increase BCL2 expression and decrease priming in Tcons. Apoptosis assays also revealed that low-dose IL-2 reduced susceptibility to apoptosis only in Tregs. ABT-199, a selective BCL2 inhibitor, enhanced the priming and apoptosis of both Tcells. IL-2 reversed the effects of ABT-199 for Tregs only. This provides further evidence that the inhibition of intrinsic pathway apoptosis mediated by IL-2 in Tregs is dependent on BCL2

Protection of Human Lung Cells against Hyperoxia Using the DNA Base Excision Repair Genes hOgg1 and Fpg

Hyperoxia causes pulmonary toxicity in part by injuring alveolar epithelial cells. Previous studies have shown that toxic oxygen-derived species damage DNA and this damage is recognized and repaired by either human enzyme 8-oxoguanine DNA glycosylase (hOgg1) or Escherichia coli enzyme formamidopyrimidine DNA glycosylase (Fpg). To determine whether these DNA repair proteins can reduce O2-mediated DNA damage in lung cells, A549 lung epithelial cells were transduced with either hOgg1 or Fpg using a retroviral vector containing enhanced green fluorescent protein. Expression of each gene in the transduced cells was confirmed by fluorescent microscopy, Northern blotting, Western blotting, and an enzymatic oligonucleotide cleavage assay. A549 cells expressing either hOgg1 or Fpg were protected from hyperoxia as evidenced by a decrease in DNA damage and a corresponding increase in cell survival. Further, we determined that overexpression of hOgg1 or Fpg partially mitigated the toxic effects of hydrogen peroxide in lung cells. Our data suggest that increased expression of DNA base excision repair genes might represent a new approach for protecting critical lung cells from the toxic effects of hyperoxia

Prognostic factors for progression of visual field deterioration in patients with primary open-angle glaucoma

Regulatory T cells (Tregs) play an important role in the maintenance of self-tolerance and immune homeostasis. Interleukin-2 (IL-2) is critical for Treg expansion, activity and survival. Previous studies have demonstrated that low-dose IL-2 resulted in the selective expansion of Tregs and the clinical improvement of auto-immune disease. To examine the mechanisms whereby IL-2 affects Treg apoptosis through the intrinsic pathway, we used BH3 profiling, and quantitated mitochondrial apoptotic priming. This pattern suggests that Tregs were more primed than conventional CD4 T cells (Tcons) in a BCL2-dependent manner. Tregs expressed lower levels of BCL2 than Tcons. To examine the functional effects of IL-2, sorted Tregs and Tcons were cultured with different concentrations of IL-2. Low-dose IL-2 (10 IU/mL) lowered priming and increased BCL2 expression in Tregs. However, higher concentrations of IL-2 (>100 IU/mL) were required to increase BCL2 expression and decrease priming in Tcons. Apoptosis assays also revealed that low-dose IL-2 reduced susceptibility to apoptosis only in Tregs. ABT-199, a selective BCL2 inhibitor, enhanced the priming and apoptosis of both Tcells. IL-2 reversed the effects of ABT-199 for Tregs only. This provides further evidence that the inhibition of intrinsic pathway apoptosis mediated by IL-2 in Tregs is dependent on BCL2

Some Considerations on Color Hologram Tiral Techniques Using He-Cd^+ Laser with Coherent Blue-White Light

Optical holography technology is now firmly established as a special display medium as well as a useful tool for scientific and engineering studies. It has found a remarkably wide range of applications such as color holography, holographic interferometry, and computer-generated holograms. A hollow dathode He-Cd+1aser with coherent blue-white light is now available in place of a He-Ne laser and an Ar^+ laser. A simple optical setup for the separation of RGB primary colors is proposed from the viewpoint of making the practical color hologram in this study. The deterioration of visual appearance of reconstructed images owing to the cross talk is discussed in connection with the recording materials with high resolution and wide spectral characteristics

Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer : A phase II study

Cisplatin plus 5‐fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5‐fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib‐III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2) and nedaplatin (50 mg/m2) on days 1 and 8, and a continuous infusion of 5‐fluorouracil (400 mg/m2/day) on days 1‐5 and 8‐12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end‐point was the completion rate of the protocol treatment. Twenty‐eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty‐five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment‐related deaths and major surgical complications did not occur. Estimated 2‐year progression‐free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305)

Trastuzumab-Based Combination Chemotherapy in Patients with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Carcinoma ex Pleomorphic Adenoma

Background: Carcinoma ex pleomorphic adenoma (CXPA) is a rare histologic subtype of lacrimal gland and submandibular gland cancer. Currently, there is no standard treatment for metastatic CXPA, although some case reports have explored the role of targeted agents in chemotherapy. A few histopathologic analyses have shown that some of these tumors overexpress human epidermal growth factor receptor-2 (HER2), suggesting a potential role for HER2-based therapy. We report here two cases of metastatic CXPA that were treated with trastuzumab-based chemotherapy (IRB approved) with rapid and significant responses. Case Report 1: A 66-year-old male was diagnosed as HER2-positive CXPA of the right lacrimal gland with multiple bone and lymph node metastases. Combination chemotherapy with trastuzumab (Tmab) and nanoparticle albumin-bound paclitaxel (nabPTX) was initiated. A rapid response was confirmed, and after seven cycles of treatment, CR(complete response) was achieved. Case Report 2: A 67-year-old female was diagnosed with HER2 positive CXPA of the right submandibular gland. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with Tmab and nab-PTX was initiated. A rapid partial response (PR) was confirmed, and she eventually became disease-free. Conclusion: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of HER2-positive CXPA, therapeutic information must be obtained from case reports. Some reports, such as this one, have suggested a potential utility of trastuzumab-based chemotherapy

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease