Advances in Retinal Tissue Engineering

Retinal degenerations cause permanent visual loss and affect millions world-wide. Current treatment strategies, such as gene therapy and anti-angiogenic drugs, merely delay disease progression. Research is underway which aims to regenerate the diseased retina by transplanting a variety of cell types, including embryonic stem cells, fetal cells, progenitor cells and induced pluripotent stem cells. Initial retinal transplantation studies injected stem and progenitor cells into the vitreous or subretinal space with the hope that these donor cells would migrate to the site of retinal degeneration, integrate within the host retina and restore functional vision. Despite promising outcomes, these studies showed that the bolus injection technique gave rise to poorly localized tissue grafts. Subsequently, retinal tissue engineers have drawn upon the success of bone, cartilage and vasculature tissue engineering by employing a polymeric tissue engineering approach. This review will describe the evolution of retinal tissue engineering to date, with particular emphasis on the types of polymers that have routinely been used in recent investigations. Further, this review will show that the field of retinal tissue engineering will require new types of materials and fabrication techniques that optimize the survival, differentiation and delivery of retinal transplant cells.     

International Hemoglobin Information Center Policies - Ihic

Abstract

The levels of the inactive hemoglobin (Hb) pigments [such as methemoglobin (metHb), carboxyhemoglobin (HbCO) and sulfohemoglobin (SHb)] and the active Hb [in the oxyhemoglobin (oxyHb) form] as well as the blood Hb concentration in healthy non pregnant female volunteers were determined using a newly developed multi-component spectrophotometric method. The results of this method revealed values of SHb% in the range (0.0727–0.370%), metHb% (0.43–1.0%), HbCO% (0.4–1.52%) and oxyHb% (97.06–98.62%). Furthermore, the results of this method revealed values of blood Hb concentration in the range (12.608–15.777?g/dL). The method is highly sensitive, accurate and reproducible.     

同型半胱氨酸对血管内皮细胞合成蛋白聚糖的影响

为探讨同型半胱氨酸对血管内皮细胞合成蛋白聚糖的影响，采用400umol／L同型半胱氨酸作用于培养的人脐静脉内皮细胞，以^35S-Na2SO4为示踪物标记细胞合成的蛋白聚糖，通过离子交换层析，凝胶过滤层析分离蛋白聚糖。结果发现，实验组培养液中总蛋白聚糖降低，硫酸乙酰肝素蛋白聚糖及硫酸软骨素-硫酸皮肤素蛋白聚糖含量也降低，但其百分含量未见改变。细胞层中蛋白聚糖未见明显变化。     

Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis

Interstitial pneumonitis (IP) associated with polymyositis and dermatomyositis (PM/DM) is a serious complication that affects prognosis. We therefore undertook a retrospective multicenter study to examine the efficacy of a combination treatment with cyclosporin A (CsA) and corticosteroids. Fifty-three IP patients with PM/DM (9 PM, 44 DM) were analyzed. Thirty-two patients treated with CsA plus corticosteroids (9 PM, 23 DM) were included in the study. Four parameters, i.e., subjective symptoms, ausculatory sound, chest radiographs, and respiratory index, were serially evaluated. A general evaluation was performed 4 weeks after the start of the combination treatment. All patients with PM and chronic IP with DM, and 52% of those with acute IP with DM were graded as better than partially effective in the general evaluation. In contrast, all patients graded as progressive in the general evaluation had acute IP with DM. It is of note that in acute IP with DM, the survival rate of the group primarily treated with CsA and corticosteroids from the early stage of their disease was significantly higher than that of the group initially treated with corticosteroids alone (P = 0.049). In conclusion, a combination treatment of CsA and corticosteroids from the early stage of disease may be advantageous for patients with IP with PM/DM, especially acute IP with DM.     

Methemoglobin Forming Effect of Dimethyl Trisulfide in Mice

Abstract

Dimethyl trisulfide (DMTS) is a natural organic trisulfide that has been patented as a promising antidotal candidate against cyanide (CN). The primary mode of action of DMTS is as a sulfur donor that enables the conversion of CN to thiocyanate. Recently, it was discovered that DMTS is capable of oxidizing hemoglobin (Hb) to methemoglobin (MetHb) in vitro. The goal of these experiments was to measure the extent of DMTS-induced MetHb formation in vivo. In these experiments, intramuscular (IM) injections of formulated DMTS were administered to mice. Following the IM injection, blood was drawn and analyzed for MetHb using a rapid spectrophotometric method. Methemoglobin levels peaked in a dose-dependent manner between 20 and 30?min., and then began dropping. The highest MetHb levels measured for the 50, 100, 200 and 250?mg/kg doses of DMTS were respectively 3.28, 6.12, 9.69, and 10.76% MetHb. These experiments provide the first experimental evidence that IM administered DMTS generates MetHb in vivo and provide additional evidence for the presence of a secondary therapeutic pathway for DMTS - CN scavenging by DMTS-generated MetHb.     

Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis

Abstract

Interstitial pneumonitis (IP) associated with polymyositis and dermatomyositis (PM/DM) is a serious complication that affects prognosis. We therefore undertook a retrospective multicenter study to examine the efficacy of a combination treatment with cyclosporin A (CsA) and corticosteroids. Fifty-three IP patients with PM/DM (9 PM, 44 DM) were analyzed. Thirty-two patients treated with CsA plus corticosteroids (9 PM, 23 DM) were included in the study. Four parameters, i.e., subjective symptoms, ausculatory sound, chest radiographs, and respiratory index, were serially evaluated. A general evaluation was performed 4 weeks after the start of the combination treatment. All patients with PM and chronic IP with DM, and 52% of those with acute IP with DM were graded as better than “partially effective” in the general evaluation. In contrast, all patients graded as “progressive” in the general evaluation had acute IP with DM. It is of note that in acute IP with DM, the survival rate of the group primarily treated with CsA and corticosteroids from the early stage of their disease was significantly higher than that of the group initially treated with corticosteroids alone (P = 0.049). In conclusion, a combination treatment of CsA and corticosteroids from the early stage of disease may be advantageous for patients with IP with PM/DM, especially acute IP with DM.     

Papillomavirus Infectious Pathways: A Comparison of Systems

The HPV viral lifecycle is tightly linked to the host cell differentiation, causing difficulty in growing virions in culture. A system that bypasses the need for differentiating epithelium has allowed for generation of recombinant particles, such as virus-like particles (VLPs), pseudovirions (PsV), and quasivirions (QV). Much of the research looking at the HPV life cycle, infectivity, and structure has been generated utilizing recombinant particles. While recombinant particles have proven to be invaluable, allowing for a rapid progression of the HPV field, there are some significant differences between recombinant particles and native virions and very few comparative studies using native virions to confirm results are done. This review serves to address the conflicting data in the HPV field regarding native virions and recombinant particles.     

Golimumab for moderate to severe ulcerative colitis

Introduction: Golimumab (GLM) is a subcutaneously administered human anti-tumor necrosis factor (TNF) agent that has been approved by the regulatory authorities for the treatment of moderate to severe ulcerative colitis (UC) in 2013.

Areas covered: Maintained clinical remission rates up to 50% have been shown in UC patients receiving GLM, and higher GLM serum concentrations have been associated with improved clinical outcomes. Approximately 50% of UC patients do not respond to induction therapy with GLM, and up to 40% of GLM responders will lose response over time. In most patients, loss of response is associated with low serum GLM concentrations, which suggests insufficient exposure to GLM. Low GLM serum concentrations may be avoided by therapeutic drug monitoring.

Expert commentary: So far, the therapeutic window for GLM has not yet been defined, but options to dose increase GLM based on therapeutic drug monitoring might result in improved clinical outcome and higher success rates.     

The Mitochondrial Permeability Transition: Role in Ischemia/Reperfusion Injury

The mitochondrial permeability transition (MPT) occurs when a non-specific pore opens in the inner mitochondrial membrane and converts the mitochondrion from an organelle whose ATP production sustains the normal function of the cell to an instrument of death. Conditions favouring the MPT including high [Ca2+], oxidative stress and adenine nucleotide depletion, all of which occur when a tissue is reperfused following a period of ischemia. Cyclosporin A (CsA) and low pH (<7.0) are potent inhibitors of the MPT. Methods have been devised to demonstrate directly that the MPT pores open upon reperfusion but not during ischemia. The mechanism of the MPT appears to involve binding of mitochondrial cyclophilin (CyP) to the adenine nucleotide translocase (ANT) followed by a calcium-mediated conformational change that converts the ANT into a non-specific pore. Understanding the molecular mechanism has assisted in devising strategies that can be used to protect tissues from damage caused by reperfusion injury. These might also be of benefit in the prevention of multiple organ failure for which reperfusion injury of the gut is thought to be the initial trigger. Protective regimes include the pretreatment of tissues prior to ischemia/reperfusion with CsA (binds to CyP), free radical scavengers that reduce oxidative stress (e.g., pyruvate and propofol) and agents that decrease pHi (e.g., pyruvate or amelioride derivatives). Reperfusion injury can produce both immediate cell death by necrosis or delayed apoptotic cell death and it appears that the mitochondria determine which route is taken. Prolonged opening leads to rapid cell death by necrosis, whilst transient opening leads to cytochrome c release and subsequent apoptosis hours or days later.     

An Overview of Molecular Aspects of Iron Metabolism

Iron (Fe) is an essential, but potentially noxious, metal for almost all organisms. Its precise cellular regulation is necessary to ensure synthesis of numerous iron-containing proteins required for metabolic processes yet at the same time avoiding the build-up of potentially toxic levels of iron. In humans, iron-deficiency results in anemia, while excess iron can lead to organ damage as a result of a build-up of non-transferrin-bound iron (NTBI). In recent years, the cloning of novel proteins has clarified the mechanisms of iron uptake, storage and metabolic regulation. Our current knowledge of the molecular aspects of mammalian iron metabolism and NTBI are presented in this review.     

Palliative management of refractory dyspnea in COPD

COPD is a progressive illness with worldwide impact. Patients invariably reach a point at which they require palliative interventions. Dyspnea is the most distressing symptom experienced by these patients; when not relieved by traditional COPD management strategies it is termed “refractory dyspnea” and palliative approaches are required. The focus of care shifts from prolonging survival to reducing symptoms, increasing function, and improving quality of life. Numerous pharmacological and non-pharmacological interventions can achieve these goals, though evidence supporting their use is variable. This review provides a summary of the options for the management of refractory dyspnea in COPD, outlining currently available evidence and highlighting areas for further investigation. Topics include oxygen, opioids, psychotropic drugs, inhaled furosemide, Heliox, rehabilitation, nutrition, psychosocial support, breathing techniques, and breathlessness clinics.     

Gastrointestinal symptoms associated with enteric-coated sulfasalazine (Azulfidine EN tablets)

Abstract

To investigate both the incidence and the dosage used to treat gastrointestinal (GI) symptoms associated with enteric-coated sulfasalazine (Azulfidine EN, AZL) in patients with rheumatoid arthritis (RA), we studied the clinical history of 153 RA patients, and any available data on GI symptoms that might have been associated with AZL. GI symptoms appeared in 64 (42.5%) of the 153 cases. There were 19 events of nausea, vomiting, or dyspepsia, 14 events each of epigastric discomfort and reduction or loss of appetite, 10 events of epigastric, stomach, or abdominal pain, 9 events of heartburn, 8 events of mouth ulcer, 3 events each of loss of taste and abdominal bloating or borborygmus, 2 events each of diarrhea or loose stools, hematemesis or melanemia, and gastric or esophageal ulcer, and 1 event of stomatitis. These results indicate that GI symptoms associated with AZL are usually mild and treatment can continue, with almost all cases responding to a reduction in dose or drug cessation. In some cases, a histamine receptor-2 blocker or proton pump inhibitor is also required.     

Efficacy and safety of bucillamine, a d-penicillamine analogue, in patients with active rheumatoid arthritis

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study.     

三七有效组分Rx对兔动脉粥样硬化的实验研究

目的：探讨三七有效组分R。对兔动脉粥样硬化的影响。方法：40只雄性新西兰大白兔随机分成正常对照组、高脂模型组、三七总皂甙组三七有效组分Rx高荆量组、三七总皂甙组三七有效组分Rx低刺量组，喂饲12周后同时处死．分别测定血一氧化氮(NO)、内皮素(ET)、PAI、t—PA、血浆脂质过氧化物、红细胞内超氧化物歧化酶(SOD)，并行主动脉壁形态学、主动脉壁光镜、透射电镜观察。结果：三七有效组分Rx高、低剂量组明显升高血NO、t—PA，降低血清ET、PAI水平，抗脂质过氧化，提高红细胞内SOD活性。大体形态、光镜、电镜显示，三七有效组分Rx高、低剂量组能减轻动脉粥样硬化病变程度，减少泡沫细胞层数。结论：三七有效组分Rx有干预动脉粥样硬化的作用。     

Efficacy and safety of bucillamine,a d-penicillamine analogue,in patients with active rheumatoid arthritis

Abstract

Japanese rheumatologists consider bucillamine (Buc) to be a useful disease-modifying antirheumatic drug (DMARD) and often give Buc to patients with rheumatoid arthritis (RA) prior to administering methotrexate (MTX). However, no large studies on the efficacy and safety of Buc in RA patients have been published in English to date. We therefore investigated the clinical course of RA patients treated with Buc and compared the results with those for patients treated with MTX to evaluate and confirm the place of Buc in therapeutic strategies for RA in Japan. Our results suggested that Buc should be given to patients with moderately active RA either before or after the administration of MTX because its efficacy can be judged within 3 months and because serious adverse events are rare. Issues like the ability of Buc to prevent joint destruction and its efficacy and safety when combined with agents like etanercept require future study.     

Identification and Characterization of Swine Influenza Virus H1N1 Variants Generated in Vaccinated and Nonvaccinated,Challenged Pigs

Influenza viruses represent a continuous threat to both animal and human health. The 2009 H1N1 A influenza pandemic highlighted the importance of a swine host in the adaptation of influenza viruses to humans. Nowadays, one of the most extended strategies used to control swine influenza viruses (SIVs) is the trivalent vaccine application, whose formulation contains the most frequently circulating SIV subtypes H1N1, H1N2, and H3N2. These vaccines do not provide full protection against the virus, allowing its replication, evolution, and adaptation. To better understand the main mechanisms that shape viral evolution, here, the SIV intra-host diversity was analyzed in samples collected from both vaccinated and nonvaccinated animals challenged with the H1N1 influenza A virus. Twenty-eight whole SIV genomes were obtained by next-generation sequencing, and differences in nucleotide variants between groups were established. Substitutions were allocated along all influenza genetic segments, while the most relevant nonsynonymous substitutions were allocated in the NS1 protein on samples collected from vaccinated animals, suggesting that SIV is continuously evolving despite vaccine application. Moreover, new viral variants were found in both vaccinated and nonvaccinated pigs, showing relevant substitutions in the HA, NA, and NP proteins, which may increase viral fitness under field conditions.     

The hypothalamic-pituitary-thyroid axis in critical illness

In severe illness, profound changes occur in the hypothalamic-pituitary-thyroid axis. The observed decrease in serum concentration of both thyroid hormones and thyrotropin (TSH) are not compatible with a negative feedback loop and suggest a major change in setpoint regulation of the hypothalamic-pituitary-thyroid axis. This is supported by post mortem studies showing a decreased expression of thyrotropin-releasing hormone in the hypothalamic paraventricular nucleus of patients with a decreased serum T3 level. In critical illness, serum T3 may even become undetectable without giving rise to an elevated concentration of serum TSH. It is currently not clearly established whether this reflects an adaptation of the organism to illness or instead a potentially harmful condition leading to hypothyroidism at tissue level. There is thus a need for randomized clinical trials in critically ill patients to investigate whether they may benefit from a normalization of thyroid hormone concentration. Recent clinical studies in these patients involving the administration of hypothalamic peptides open up new ways of achieving this.     

慢型、潜在型克山病患者的血管内皮功能观察

目的观察山东省慢型、潜在型克山病患者的临床特点和血管内皮功能,探讨机体内皮功能失调与克山病发生发展的关系。方法选择慢型、潜在型克山病患者57人、病区健康人34人,分别采集清晨空腹血检测ET、NO、NOS、iNOS及cNOS含量及活性。结果(1)克山病患者ET水平明显高于病区健康人(P<0.01);心功能越差,ET升高越明显(P<0.01);(2)NO和NOS含量,潜在型、慢型克山病均明显高于病区健康人(P<0.01);慢型高于潜在型(P<0.01);iN-OS含量克山病患者也高于病区健康人(P<0.05);慢型克山病高于潜在型克山病(P<0.05)。结论ET、NO水平的变化可能作为一种中间环节参与了克山病的发病机制;心功能不同,血浆ET、NO升高的程度也不同;ET、NO可作为克山病病情严重程度的预测指标。     

Variability in the anti-tumor effect of tegafur-uracil depending on histologic types of lung cancer

Background

Tegafur-uracil (UFT) is an anticancer agent that inhibits thymidylate synthase (TS). The degree of TS expression in primary lung cancer (LC) is different according to histologic cell type. In this study, we examined the variability of the anti-tumor efficacy of UFT monotherapy depending on histological subtypes of LC.

Methods

In the current single-institution, retrospective study, we assigned the patients with LC to three histologic groups [the squamous (Sq) non-small cell lung cancer (NSCLC)] group, the non-Sq NSCLC group and the SCLC group] and then compared the clinical response to UFT monotherapy between the three groups.

Results

Our clinical series of 149 patients include 54 cases of Sq NSCLC, 67 cases of non-Sq NSCLC and 28 cases of SCLC. For Sq NSCLC, non-Sq NSCLC and SCLC group, the overall response rates (ORRs) were 1%, 1% and 0% (P=0.522), respectively. The disease control rates (DCRs) were 38.9%, 31.3% and 10.7% (P=0.012), respectively. The median progression-free survivals (PFSs) were 2.68, 2.25 and 1.46 months (P=0.004 for three groups and P=0.773 for two groups except for the SCLC group at the log-rank test), respectively. There was no significant difference between the groups in median overall survival (OS).

Conclusions

Our results indicate that the degree of the anti-tumor effect of UFT was higher in patients with NSCLC as compared with SCLC. But it showed no significant difference between the patients with Sq NSCLC and those with non-Sq NSCLC.