Dubin-Johnson综合征1例

Dubin-Johnson综合征是一种先天性非溶血性黄疸,在临床中较罕见,需与其他原因所导致的黄疸相鉴别.本文报告了我院1例Dubin- Johnson综合征的诊治情况,有助于加深对该病的认识.     

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium : Implications for Age-Related Macular Degeneration

Retinal pigment epithelium (RPE)-derived membranous debris named blebs, may accumulate and contribute to sub-RPE deposit formation, which is the earliest sign of age-related macular degeneration (AMD). Oxidative injury to the RPE might play a significant role in AMD. However, the underlying mechanisms are unknown. We previously reported that hydroquinone (HQ), a major pro-oxidant in cigarette smoke, foodstuff, and atmospheric pollutants, induces actin rearrangement and membrane blebbing in RPE cells as well as sub-RPE deposits in mice. Here, we show for the first time that phosphorylated Heat shock protein 27 (Hsp27), a key regulator of actin filaments dynamics, is up-regulated in RPE from patients with AMD. Also, HQ-induced nonlethal oxidative injury led to Hsp27mRNA up-regulation, dimer formation, and Hsp27 phosphorylation in ARPE-19 cells. Furthermore, we found that a cross talk between p38 and extracellular signal-regulated kinase (ERK) mediates HQ-induced Hsp27 phosphorylation and actin aggregate formation, revealing ERK as a novel upstream mediator of Hsp27 phosphorylation. Finally, we demonstrated that Hsp25, p38, and ERK phosphorylation are increased in aging C57BL/6 mice chronically exposed to HQ, whereas Hsp25 expression is decreased. Our data suggest that phosphorylated Hsp27 might be a key mediator in AMD and HQ-induced oxidative injury to the RPE, which may provide helpful insights into the early cellular events associated with actin reorganization and bleb formation involved in sub-RPE deposits formation relevant to the pathogenesis of AMD.Age-related macular degeneration (AMD) is the main cause of blindness in the elderly population in the Western societies and has a devastating impact on people’s quality of life.^1,2,3,4 An estimated 13 million Americans have some degree of AMD and unless better preventive treatments emerge, this number is expected to climb and even reach epidemic proportions with the overall aging demographics. Although the cause of AMD has not yet been fully determined, this complex multifactorial disease clearly results from the interplay of multiple genetic and environmental risk factors^2,5 that lead to progressive destruction of retinal pigment epithelial (RPE) cells and photoreceptors and ultimately to vision loss.Accumulation of deposits between the RPE and its basement membrane (called basal laminar deposits) is part of the numerous biochemical and anatomical changes associated with aging retina. However, the presence of large numbers and extensive areas of additional deposits (named basal linear deposits and drusen) beneath the RPE and within the inner collagenous layer of Bruch’s membrane (BrM) is a defining histopathological landmark associated with dry AMD,⁶ the most common type of the disease that affects the greatest number of people. Until now, the underlying pathogenic mechanisms of sub-RPE deposits formation and accumulation as well as their relative contribution to the pathogenesis of AMD are still obscure. However, a growing body of evidence suggests that cumulative oxidative injury is implicated in the pathogenesis of the disease^7,8,9 and plays a critical role in deposits formation.¹⁰ Cigarette smoking is a major source of oxidative stress and has unequivocally been established as the single greatest environmental risk factor in the onset and development of AMD.^11,12,13,14 It has been suggested that cigarette smoking might contribute to the pathogenesis of AMD by causing oxidative damage to the RPE.¹⁵ Tar within cigarette smoke contains a large number of pro-oxidant compounds among which hydroquinone (HQ) is the most abundant. HQ is an oxidant of special relevance due to its presence not only in cigarette smoke but also in processed foods, plastic containers, and atmospheric pollutants as well as its widespread occurrence in nature.^16,17 Detectable levels of HQ have been measured in the plasma of many nonsmoker individuals living a Western life style.¹⁶We embrace the pathogenic paradigm based on the response-to-injury hypothesis, which proposes that sub-RPE deposits originate from RPE-derived cell membrane blebs^18,19 induced by chronic nonlethal injury to the RPE in response to oxidative damage. Clinical studies performed on eyes from patients with AMD have revealed that membranous debris from the basolateral RPE surface traversed the RPE membrane and deposited in the inner and outer collagenous layers of BrM.²⁰ We previously found that exposure to cigarette smoke and HQ resulted in RPE membrane blebbing and sub-RPE deposits in mice.^21,22 We also demonstrated that nonlethal HQ-induced oxidative injury in cultured RPE cells results in reorganization of actin cytoskeleton and blebs formation^22,23,24,25 relevant to the accumulation of deposits. Blebbing of the plasma membrane is an early morphological sign of cell injury, which occurs immediately after exposure to a wide variety of toxic agents. Oxidative stress induces profound rearrangements of the actin cytoskeleton^26,27,28 leading to membrane blebbing through the activation of p38 mitogen activated protein kinase (MAPK)/Heat shock protein 27 (Hsp27) pathway.^26,29Hsp27 (Hsp25 in mice) is a phosphorylation-regulated filamentous actin (F-actin) cap binding protein that plays a key role in modulating actin microfilaments dynamics.³⁰ We previously reported that ARPE-19 cells constitutively express high levels of Hsp27, which are regulated by oxidant-mediated injury.³¹ We also found that Hsp27 is expressed in extruded blebs confirming that Hsp27 plays a role in actin filaments dynamics. In addition, we demonstrated that prolonged exposure of RPE cells to HQ results in actin rearrangements into aggregates and membrane blebbing, with a concomitant activation of the p38 MAPK pathway showed by immunohistochemistry.²⁵ However, whether HQ-induced oxidative injury can activate other MAPK signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2) cascade, has not been investigated. In addition, this study did not address the question of any posttranslational modifications such as dimerization and phosphorylation of Hsp27 known to regulate F-actin polymerization. Taken together, these data suggest that Hsp27 may be an important mediator of RPE response to HQ-induced oxidative damage and may contribute to injury-induced actin rearrangement and blebbing, which may be crucial in the formation of sub-RPE deposits. The aim of this study was to evaluate the expression of phosphorylated Hsp27 in RPE from patients with AMD and further characterize the contribution of phosphorylated Hsp27 in mediating F-actin cytoskeleton reorganization during nonlethal HQ-induced oxidative stress as well as the involvement of p38 and ERK MAPK pathways. A greater understanding of the sequence of early cellular events associated with HQ-induced F-actin dysregulation in RPE cells is of critical importance to further identify its role in the regulation of RPE blebbing and define its contribution to the accumulation of sub-RPE deposits relevant to the pathophysiology of AMD.     

Rapid Subcutaneous IgG Replacement Therapy is Effective and Safe in Children and Adults with Primary Immunodeficiencies—A Prospective, Multi-National Study

Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 (1%) systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.     

Tratamiento del dolor anal por patología anorrectal aguda en urgencias: ¿baños de asiento con agua fría o caliente? resultados de un ensayo clínico aleatorizado

IntroductionThe popular belief advocates the use of sitz (sitting) baths with cold water for the treatment of acute anal pain, but clinical practice guides recommend the use of hot water for its known effect on the at-rest anal pressure.AimThe objective of the study was to examine the analgesic effect on the quality of life, manometer data and clinical progress, of the two temperatures in sitz baths in patients with anal pain.Material and methodsA randomised clinical trial on patients with acute anal pain due to haemorrhoids or anal fissures, divided into Group 1: Sitz baths with water at a temperature of less than 15 °C, and Group 2: Baths with a water temperature above 30 °C. The analgesia was the same in both groups. An analysis was made of the pain at 7 days (visual analogue scale), quality of life (SF-36), anal at-rest pressure and disease progress.ResultsOf the 27 eligible patients, 24 were randomised (Group 1: n=12 y Group 2: n=12). There were no statistical differences in pain, but it remained stable in Group 1, but gradually decreased in the patients of Group 2, the difference being in the pain scores on the first day compared to the seventh in Group 2 (p=0.244). The rest of the variables were similar.ConclusionThere were no statistically significant differences in pain control from day 1 to day 7 in the Group with sitz baths with hot water.(ISRCTN Number: 50105150).     

Tocolysis and delayed delivery versus emergency delivery in cases of non-reassuring fetal status during labor

AIM: To determine whether fetal intrauterine resuscitation using tocolysis and delayed delivery is better for the fetus than emergency delivery when fetal hypoxia is suspected because of a non-reassuring fetal heart-rate (FHR) pattern using conventional heart rate monitoring. METHODS: This was a prospective and randomized study, conducted between 2001 and 2004 at Pereira Rossell Hospital, Montevideo, Uruguay. The population consisted of 390 fetuses, in which intrauterine distress was diagnosed using electronic FHR monitoring. Of these, 197 were randomly assigned to the emergency delivery group and 193 to the fetal intrauterine resuscitation group. The inclusion criteria were: term singleton pregnancy, in labor, cephalic presentation, and no placental accidents. RESULTS: The time between randomization and birth was 16.9 +/- 7.6 min (mean +/- SD) for the emergency delivery group, and 34.5 +/- 11.7 min (mean +/- SD) for the resuscitation group. The relative risk (RR) of acidosis in the umbilical artery (pH < 7.1) in the emergency delivery group was 1.47 (0.95-2.27). The RR of base deficit < or =12 mEq/L in the emergency delivery group was higher than in the resuscitation group (RR = 1.48 [1.0-2.2], P = 0.04). When considering the need for admission to the neonatal care unit, the relative risk was higher in the emergency delivery group than in the resuscitation group (RR = 2.14 [1.23.3.74], P = 0.005). No maternal adverse effects were reported. CONCLUSION: Tocolysis and delayed delivery renders better immediate neonatal results than emergency delivery when fetal distress is suspected because of a non-reassuring fetal heart pattern. In addition, it may decrease the need for emergency delivery without increasing maternal and fetal adverse side-effects.     

Multiplex PCR targeting tpi (triose phosphate isomerase), tcdA (Toxin A), and tcdB (Toxin B) genes for toxigenic culture of Clostridium difficile

A multiplex PCR toxigenic culture approach was designed for simultaneous identification and toxigenic type characterization of Clostridium difficile isolates. Three pairs of primers were designed for the amplification of (i) a species-specific internal fragment of the tpi (triose phosphate isomerase) gene, (ii) an internal fragment of the tcdB (toxin B) gene, and (iii) an internal fragment of the tcdA (toxin A) gene allowing distinction between toxin A-positive, toxin B-positive (A+B+) strains and toxin A-negative, toxin B-positive (A−B+) variant strains. The reliability of the multiplex PCR was established by using a panel of 72 C. difficile strains including A+B+, A−B−, and A−B+ toxigenic types and 11 other Clostridium species type strains. The multiplex PCR assay was then included in a toxigenic culture approach for the detection, identification, and toxigenic type characterization of C. difficile in 1,343 consecutive human and animal stool samples. Overall, 111 (15.4%) of 721 human samples were positive for C. difficile; 67 (60.4%) of these samples contained A+B+ toxigenic isolates, and none of them contained A−B+ variant strains. Fifty (8%) of 622 animal samples contained C. difficile strains, which were toxigenic in 27 (54%) cases, including 1 A−B+ variant isolate. Eighty of the 721 human stool samples (37 positive and 43 negative for C. difficile culture) were comparatively tested by Premier Toxins A&B (Meridian Bioscience) and Triage C. difficile Panel (Biosite) immunoassays, the results of which were found concordant with toxigenic culture for 82.5 and 92.5% of the samples, respectively. The multiplex PCR toxigenic culture scheme described here allows combined diagnosis and toxigenic type characterization for human and animal C. difficile intestinal infections.     

Higher-order organization and compartmentalization of satellite DNA PIM357 in species of the coleopteran genus Pimelia

The PIM357 satellite DNA family is present in 26 Pimelia taxa (Tenebrionidae, Coleoptera) with endemic congeneric species from the Canary Islands showing higher interrepeat variability than continental ones. In this paper, we compare the repetitive DNA sequences of a Canarian species that has distinct subfamilies of repeat units, P. radula ascendens, with another without such subfamilies, P. sparsa sparsa. The chromosomal localization of the repeat units and the comparison of the variability of randomly cloned monomers to the one estimated by comparing repeat units from dimers and trimers suggest the absence of satellite subfamilies in P. sparsa sparsa. Hence, the repeat units of this species seem to be uniformly and randomly distributed throughout all chromosomes out of one chromosomal pair. On the contrary, P. radula ascendens shows four divergent subfamilies of repeat units supported by several diagnostic nucleotide substitutions. These subfamilies seem to form four distinct repeat units: monomer subfamily 1, monomer subfamily 4 and two higher-order units (dimer linking subfamily 1 and 4, and dimer linking subfamily 2 and 3). Moreover, monomers of subfamily 1 are present in three chromosomal pairs only. We discuss the effect of different potential factors acting in the concerted evolution and the genomic organization of stDNA sequences in these taxa. This revised version was published online in July 2006 with corrections to the Cover Date.     

Towards immunotherapy for peanut allergy

PURPOSE OF REVIEW: Food allergy is a major cause of life-threatening hypersensitivity reactions. Peanut allergy is the most serious of the hypersensitivity reactions to foods due to its persistence and high risk of severe anaphylaxis. Currently, strict avoidance of the allergenic food and ready access to self-injectable epinephrine is the 'standard of care' for food allergy. Based on extensive characterization of food allergens and a better understanding of the immunological mechanisms underlying allergic disease, promising therapeutic modalities for food allergy treatment and prevention are being developed. RECENT FINDINGS: Immunotherapeutic strategies include peptide immunotherapy, mutated protein immunotherapy and DNA immunization, which all strive to decrease the deleterious Th2 response. Another approach already in clinical trials for peanut allergy is the anti-IgE therapy which prevents circulating IgE from binding to effector cells, consequently decreasing clinical symptoms after peanut ingestion. In order to be applicable, these strategies must be well tolerated, inexpensive and easily administered. Realistic treatment options would likely involve a combination of different approaches. SUMMARY: Food allergy affects approximately 4-6% of children and 3-4% of adults. Peanut allergy can be devastating as reactions range from urticaria to severe anaphylactic shock and death. The only preventive measure for peanut allergy is strict avoidance of the incriminating food. It is likely immunotherapy will be available in the near future as a well tolerated and effective therapy for treating peanut allergy. The use of the anti-IgE therapy in conjunction with other immunotherapy would possibly be the best treatment option in the future.