变黑白头翁提取物降低亚砷酸盐对小鼠精细胞的毒性

目的：研究变黑白头翁提取物降低亚砷酸盐对小鼠精细胞毒性的作用。方法：给予实验小鼠亚砷酸钠（20mg／kg每日），并分别在第30、60、90天对小鼠进行检测。亚砷酸盐中毒小鼠被分为2组，其中一组给予变黑白头翁提取物（35mg／kg），另一组给予85％乙醇。通过检测小鼠精细胞凋亡标志蛋白CYP1A1、p53及caspase3的活性，确定细胞及DNA的损伤情况，并测定睾丸毒性标志物的水平。通过圆二色光谱仪及熔化温度数据检测变黑白头翁提取物与DNA的相互作用情况。结果：亚砷酸盐中毒小鼠的所有细胞凋亡标志蛋白及睾丸毒性标志物的水平均有所上升，而经变黑白头翁提取物治疗的小鼠上述各项指标均降低或恢复至正常水平。变黑白头翁提取物与DNA相互作用，引起了DNA结构和构象的变化。结论：变黑白头翁提取物可作为砷中毒引起的生殖功能损害的治疗药物给予研究和开发。     

Antibody-Secreting Cell Responses after Vibrio cholerae O1 Infection and Oral Cholera Vaccination in Adults in Bangladesh

Infection with Vibrio cholerae and oral cholera vaccines (OCVs) induce transient circulating plasmablast responses that peak within approximately 7 days after infection or vaccination. We previously demonstrated that plasmablast responses strongly correlate with subsequent levels of V. cholerae-specific duodenal antibodies up to 6 months after V. cholerae infection. Hence, plasmablast responses provide an early window into the immunologic memory at the mucosal surface. In this study, we characterized plasmablast responses following V. cholerae infection using a flow cytometrically defined population and compared V. cholerae-specific responses in adult patients with V. cholerae O1 infection and vaccinees who received the OCV Dukoral (Crucell Vaccines Canada). Among flow cytometrically sorted populations of gut-homing plasmablasts, almost 50% of the cells recognized either cholera toxin B subunit (CtxB) or V. cholerae O1 lipopolysaccharide (LPS). Using a traditional enzyme-linked immunosorbent spot assay (ELISPOT), we found that infection with V. cholerae O1 and OCVs induce similar responses to the protein antigen CtxB, but responses to LPS were diminished after OCV compared to those after natural V. cholerae infection. A second dose of OCV on day 14 failed to boost circulating V. cholerae-specific plasmablast responses in Bangladeshi adults. Our results differ from those in studies from areas where cholera is not endemic, in which a second vaccination on day 14 significantly boosts plasmablast responses. Given these results, it is likely that the optimal boosting strategies for OCVs differ significantly between areas where V. cholerae infection is endemic and those where it is not.     

Antioxidative Potential of Duranta Repens (Linn.) Fruits Against H2O2 Induced Cell Death In Vitro

The effects of Duranta repens fruits were investigated on H₂O₂ induced oxidative cell death to evaluate its antioxidative potential in vitro. HEK293T cells were treated with different concentrations [0–1000 µg/ ml] of ethanol extract (E-Ex) and methanol extract (M-Ex) of D. repens for 24h, and then treated with 100 µM H₂O₂ for 24h. Cell viability, antioxidant parameters of cells, and antioxidant constituents of the extracts were determined. Treatment with limited dose of E-Ex or M-Ex increased the survival rate of H₂O₂-treated HEK293T cells, however the extra-high dose showed growth inhibitory effect. Treatment with E-Ex or M-Ex protected cellular lipid per-oxidation. In vitro analyses showed the 2,2-diphenyl-1-picrylhydrazyl and H₂O₂ scavenging activities as well as reducing potential of the extracts. We report here that the limited dose of E-Ex and M-Ex possess antioxidative potential, which can protect H₂O₂-induced oxidative cell damage.     

Clinical pharmacy services in the emergency department

The emergency department (ED) is a fast-paced, high-risk, and often overburdened work environment. Formal policy statements from several notable organizations, including the American College of Emergency Physicians (ACEP) and the American Society of Health-System Pharmacists (ASHP), have recognized the importance of clinical pharmacists in the emergency medicine (EM) setting. EM clinical pharmacists work alongside emergency physicians and nurses at the bedside to optimize pharmacotherapy, improve patient safety, increase efficiency and cost-effectiveness of care, facilitate antibiotic stewardship, educate patients and clinicians, and contribute to scholarly efforts. This paper examines the history of EM clinical pharmacists and associated training programs, the diverse responsibilities and roles of EM clinical pharmacists, their impact on clinical and financial outcomes, and proposes a conceptual model for EM clinical pharmacist integration into ED patient care. Finally, barriers to implementing EM clinical pharmacy programs and limitations are considered.     

Nurturing Empathy: An Oncologist Looks at Medicine and Himself

Empathy in medicine matters. A doctor reflects on his experience as a patient and the need for clinicians to re-engage with patients empathically while giving the best care possible. In addition, we must begin teaching our students and trainees medical humanities as early as we can, because empathy can be nurtured.Empathy in medicine matters. I should know—I have been a practicing oncologist for 35 years—but it was only when, in a matter of seconds, I went from doctor to patient that I grasped its true significance.A hiking trail that I had taken for granted for years betrayed me one day. The stones on a steep path that felt solid beneath my feet suddenly shifted, and I slipped hard, slid fast, and fell off a cliff. My right foot landed on a rock slab, crushing my right ankle badly, with five fractures.I was taken to the emergency room of the hospital where I worked. My orthopedic colleague, Dr. R, took me to surgery, but as a result of excessive and traumatic swelling of the joint, he could not repair my ankle. He explained that cutting through the edematous muscles and tissues would impede healing and increase the chance of infection. He was only able to temporarily stabilize my fractures using an external fixator, for which metal-alloy rods were drilled through my heel bone below and the shinbone above and then fastened together by bolts and screws. He explained that the definitive surgery would take place only after the swelling was gone. “The next operation won’t be easy, though,” he warned me, “so I am referring you to an ankle orthopedist, Dr. M,” who I knew practiced in a large medical center in a city far from ours.Seeing my alarm, Dr. R softened his tone. “Just try to put up with pain for a while,” he said. “It’s not pancreatic cancer, you know. You will get better in time.”I was not sure how to react to his words, which were meant to comfort me. It is true what he said—I was far luckier than any of my patients with pancreatic cancer—but that thought also brought some unpleasant memories of how some of my patients with pancreatic cancer had suffered. Would I suffer the same pain as my unfortunate patients, no matter how temporary? How capricious would my pain be? Doctors sometimes say things without thinking, and heaven knows how many times I may have said similar things myself in my own practice.It was through my experience after sustaining this injury that I became aware of the behavior of some clinicians—of some colleagues—that I still find incomprehensible. After their initial bursts of concern, they forgot to check on my welfare. We could tolerate the incompetence of our colleagues (as long as it is feasible), yet when it comes to those who are handicapped, there is a certain lack of empathy. Psychiatrist Howard Shapiro put it best: “Handicapped doctors are treated like drug addicts,” he said. “Get them out of sight.”Although it was not easy, I assiduously followed Dr. R’s advice to reduce my swelling: diligent wound care and the constant elevation of my foot on four to six pillows day and night. My edema subsided, but the hardware attached to my foot was taxing and painful. I had access to narcotics, but they made things worse. I found that the codeine combinations dulled my brain and caused nausea and abdominal bloating.Ultimately, I saw that Dr. M, the ankle orthopedist, was my best chance of freedom and rescue from the current situation, and I made the difficult trip to see him. As a fellow physician, I assumed he would surely empathize and understand my suffering.To my shock, my belief and relief proved utterly wrong. He was unfeeling and appeared more interested in my fractures than in me. It was as if he had failed to notice that the joint was attached to a living being. He did not bother to touch me and was aloof with regard to the concerns I raised. I got the feeling that, to him, I was just a technical challenge and nothing more.“I have looked at your x-rays and scans,” he informed me, “and you have a hell of a lot of fractures.” He then scheduled my surgery. I told him I was an oncologist, unsure if he was aware of my profession. “That won’t change your surgery,” he said.After I settled in a hospital bed, a young doctor came to my bedside. “I am an orthopedic resident assisting Dr. M today,” he said. He wanted to discuss one of my medications, an anticoagulant. “Why are you taking it?” he asked. “Did you have thrombophlebitis?” Then he was blunt: “Have you stopped it? We can’t do surgery if you haven’t. We can’t risk hemorrhage on the operating table.”I was glad that he was careful about me before the operation. I assured him that I did not have thrombophlebitis and that my local orthopedist gave me the drug in the hope of preventing it. I also told him that I had stopped it before coming in, as I was advised. Those were all the answers the young doctor was interested in, and he did not ask me any more questions about my health. He, too, didn’t even touch me. I could see that the young doctor was copying his mentor, Dr. M, well. The former’s only concern seemed to be the anticoagulant that was noted in my record.When the resident finished, a nurse gave me an injection. After that, I did not know what had happened until I woke up in the recovery room. I was confused at first and wondered why I was in this strange place. Then I noticed a familiar face—it was Ara, my wife. “You have been in the recovery unit for 6 hours waiting to get a room on the floor,” she said. “Surgery went fine.” I reflexively looked at my right leg. It had a white cast, and the hardware was gone.I realized that Ara had been sitting by my side all through this time except when I was on the operating table. I felt a pang of guilt. A vivacious, beautiful woman who looked elegant had become haggard, her eyes sunken, face dry. What had I done to her? Why had I gone for that cursed hike?Finally, I got a room at midnight. By then I had begun to experience pain again, but this pain was of another kind, gnawing and oppressive. As the muscles and tissues of my operated ankle swelled more and more because of the cutting, they were compressed by the hard cast surrounding them. It felt worse than when I had the fixator, which at least provided room for the swelling to expand. I wanted to forestall the pain’s ascending severity. I pressed the call button for the nurses to get an injection of morphine with an antinausea medication.“Someone made a mistake in keying in your narcotics,” a nurse said. “I have called for a reorder.” Then there was more delay. “Only one pharmacist is on call at night,” she informed me. “He is swamped, and dispensing morphine has stringent rules.” She was genuinely sorry and offered me an oral codeine combination, which I accepted, but all it did was make me more miserable with nausea and abdominal bloating and little pain relief. Soon the pain got more severe, and I felt like a condemned prisoner without hope. By the time a nurse give me a narcotic injection, it was at about 3 a.m.—3 hours after my request.Following the injection of morphine, I became peaceful and went to sleep. I wished I had stayed that way, but I was startled awake at 6 a.m., after Dr. M came in for his morning rounds. Without so much as a “good morning,” he held up an x-ray in front of me. “Here is a copy of your x-ray after surgery,” he said and then went on to quickly describe what he had done. “I have put in 2 plates and 14 screws to align the bones and some bone grafts to fill the gaps.”My eyes were blurry from the light, and I was still hazy from anesthesia, exhaustion, and narcotics. I could not take it all in at the time and only later understood what happened, with my wife’s help. After he finished telling me what he had done, he hurried to leave my room. Holding the doorknob on his way out, he said, “You can go home this morning.”I hadn’t even had a chance to tell him about my ordeals at night. Ara, concerned about my pain and debility, pleaded my case: “He is too sick to travel, and we live far away.” Dr. M did not appear moved by what she said and barely talked to her. “He can rest in a hotel as well as he can in the hospital,” he replied. “I will check him in the office in 2 days.”“You can talk to the discharge planner,” he added, as he walked off.I later discovered that he had admitted me as an outpatient case, and I had already spent the required night. One might read this story and see how unfair this discharge was and that I had the right to complain about it; however, when you are sick, you are vulnerable, doctor or not. You sign all the forms a hospital puts in front of you because you have to, and this absolves the hospital of any questionable conduct.I wish I could say that my experience was unique in patient care, but it’s not. I think I would be correct in assuming that numerous patients would identify with me. Sadly, as I looked back at my practice, I saw that Dr. M’s behavior is partially explained by the silence of our colleagues. After all, neither I nor the other physicians had ever reproached another who had fallen short on bedside compassion.True, the advances in specialization and technology are saving lives or improving the quality of our lives, as they did mine. And my doctor was technically accomplished. Still, empathy is an integral part of care. Lack of empathy obviously compounds the distress of the patients, but what is not obvious is that it can have corrosive effects on the doctor’s mindset. Nine medical specialty groups have found that 45 procedures and tests currently performed by doctors have no demonstrable benefit or can be harmful to patients. Although some tests and treatments are done with good intentions, others, unfortunately, might be done for reasons that are less than altruistic. I believe that an empathic physician would try very hard not to subject his or her patients to tests or treatments with little benefit for them.If we are to preserve our voice in health care, we clinicians must re-engage with our patients empathically while giving our best care possible. Otherwise, the public will become increasingly disenchanted. In time, they may put greater demands on us, demands that are less than empathetic to our complaints about medical practice.Equally important, we must begin teaching our students and trainees medical humanities as early as we can. The humanities should not be optional but rather a standard part of the curriculum. I believe this is important because empathy can be nurtured. Ample stories in the literature illuminate the subject of medical education. An example is Anton Chekhov’s classic short story “Ward No. 6,” in which a doctor who was indifferent to the dehumanizing treatments of his patients ends up, by quirk of fate, being a patient in his own hospital. He is horrified by the pain and indignities heaped on him, the same pain and indignities his patients suffered routinely for years under his watch. A terrible, agonizing thought torments him: “How could it have happened that for more than twenty years he had not known it and had refused to know it?” Any medical student who is asked to contemplate this cannot help but get some sense of empathy for patients.     

RAGE: a new frontier in chronic airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.     

Can T1w/T2w ratio be used as a myelin‐specific measure in subcortical structures? Comparisons between FSE‐based T1w/T2w ratios,GRASE‐based T1w/T2w ratios and multi‐echo GRASE‐based myelin water fractions

Given the growing popularity of T₁‐weighted/T₂‐weighted (T₁w/T₂w) ratio measurements, the objective of the current study was to evaluate the concordance between T₁w/T₂w ratios obtained using conventional fast spin echo (FSE) versus combined gradient and spin echo (GRASE) sequences for T₂w image acquisition, and to compare the resulting T₁w/T₂w ratios with histologically validated myelin water fraction (MWF) measurements in several subcortical brain structures. In order to compare these measurements across a relatively wide range of myelin concentrations, whole‐brain T₁w magnetization prepared rapid acquisition gradient echo (MPRAGE), T₂w FSE and three‐dimensional multi‐echo GRASE data were acquired from 10 participants with multiple sclerosis at 3 T. Then, after high‐dimensional, non‐linear warping, region of interest (ROI) analyses were performed to compare T₁w/T₂w ratios and MWF estimates (across participants and brain regions) in 11 bilateral white matter (WM) and four bilateral subcortical grey matter (SGM) structures extracted from the JHU_MNI_SS ‘Eve’ atlas. Although the GRASE sequence systematically underestimated T₁w/T₂w values compared to the FSE sequence (revealed by Bland–Altman and mountain plots), linear regressions across participants and ROIs revealed consistently high correlations between the two methods (r² = 0.62 for all ROIs, r² = 0.62 for WM structures and r² = 0.73 for SGM structures). However, correlations between either FSE‐based or GRASE‐based T₁w/T₂w ratios and MWFs were extremely low in WM structures (FSE‐based, r² = 0.000020; GRASE‐based, r² = 0.0014), low across all ROIs (FSE‐based, r² = 0.053; GRASE‐based, r² = 0.029) and moderate in SGM structures (FSE‐based, r² = 0.20; GRASE‐based, r² = 0.17). Overall, our findings indicated a high degree of correlation (but not equivalence) between FSE‐based and GRASE‐based T₁w/T₂w ratios, and low correlations between T₁w/T₂w ratios and MWFs. This suggests that the two T₁w/T₂w ratio approaches measure similar facets of subcortical tissue microstructure, whereas T₁w/T₂w ratios and MWFs appear to be sensitized to different microstructural properties. On this basis, we conclude that multi‐echo GRASE sequences can be used in future studies to efficiently elucidate both general (T₁w/T₂w ratio) and myelin‐specific (MWF) tissue characteristics.     

Unusual cause of neonatal cyanosis

We present a case of a full-term female neonate who presented at 6 h of age with severe cyanosis and was partially responsive to oxygen supplementation. An echocardiogram showed an isolated congenital severe tricuspid valve insufficiency due to rupture of the papillary muscle of the anterior tricuspid valve leaflet. Magnesium sulfate was infused to lower the pulmonary resistance and thus enhancing the antegrade pulmonary blood flow. Ductal patency was secured by prostaglandin infusion thus providing an additional pulmonary blood flow through the ductus arteriosus.The above measures were adequate to stabilize the patient with no further deterioration or the need for other supportive measures such as Nitric Oxide therapy or extracorporeal membrane oxygenation (ECMO). Therefore, early diagnosis and adequate measures to improve the pulmonary blood flow are mandatory, important pre-operative measures in the management of these patients.