Constrictive pericarditis as first manifestation of neoplasia. Two cases

We report two cases of constrictive pericarditis revealing neoplasia. Both patients underwent pericardiotomy with drainage and biopsy that did not disclose malignancy. Likewise, the initial radiologic were not suggestive of cancer.     

肾移植受者T细胞亚群绝对计数动态监测对感染的预警作用

目的探讨长期监测T细胞亚群绝对计数水平对肾移植受者术后感染的预警作用。 方法回顾性分析2017年1月至2021年5月在上海交通大学医学院附属瑞金医院26例行肾移植术后新发感染受者临床资料(感染组,感染发生在移植后1～240个月)。选择129例同期肾移植术后无感染、健康受者作为对照组。感染组连续或定期测量外周血T细胞亚群CD3^＋、CD4^＋和CD8^＋绝对计数,并与对照组检测数据进行比较。根据移植后采样时间将感染组和对照组各分为6个亚组,分析感染亚组与其相应对照亚组之间T细胞亚群绝对计数的差异。正态分布计量资料采用两独立样本t检验和单因素方差分析比较,非正态分布计量资料采用Mann-Whitney U检验比较,计数资料采用χ²检验比较。使用受试者工作特征(ROC)曲线分析T细胞亚群绝对计数在肾移植术后预警感染性疾病的最优值。P<0.05为差异有统计学意义。 结果感染组和对照组受者CD4^＋/CD8^＋比值分别为(1.2±0.5)、(1.3±0.6),差异无统计学意义(t＝0.610,P>0.05)。感染组受者CD3^＋、CD4^＋和CD8^＋ T细胞绝对计数[(367±212)、(189±117)和(161±92)个/μL]均低于对照组[(1 374±663)、(695±334)和(626±377)个/μL],差异均有统计学意义(t＝14.036、13.541和12.311,P均<0.05)。CD3^＋、CD4^＋和CD8^＋ T细胞绝对计数在6个感染亚组受者中差异均无统计学意义(P均>0.05)。对照亚组1受者CD3^＋、CD4^＋和CD8^＋ T细胞绝对计数均低于对照亚组5,差异均有统计学意义(P均<0.05)。CD4^＋、CD8^＋和CD3^＋绝对计数预测肾移植术后感染性疾病最优截断值分别为712、362和255个/μL,敏感度分别为94.6%、92.2%和96.1%,特异度分别为92.3%、96.2%和88.5%。 结论肾移植受者低T细胞亚群绝对计数水平具有预示及预警感染风险的作用。     

Regulating Traditional Mexican Midwifery: Practices of Control,Strategies of Resistance

ABSTRACT

The institutionalization of Mexican midwifery has a long history. Despite global recommendations moving away from training traditional midwives, training courses still continue. Based on fieldwork in the State of Chiapas, I argue that while ongoing trainings offered to traditional midwives in Mexico aim at teaching them best practices, they also limit midwives’ autonomy and keep poor women’s reproductive behaviors under control. I demonstrate how midwives and medical personnel mobilize discourses of reproductive risk, women’s rights and indigenous cultural rights to reinforce or contest mechanisms of reproductive governance.     

Incidence of Renal and Liver Rejection and Patient Survival Rate Following Combined Liver and Kidney Transplantation

Multiple organ transplantations are used to treat chronic multiple organ failure. However, long-term mortality and graft tolerance remain to be evaluated. We carried out a retrospective and comparative analysis of 45 patients who underwent a combined liver and kidney (LK) transplantation (LKT) from the same donor. They were compared to 86 matched patients who underwent kidney (K) transplantation (KT). All patients had an organic renal failure associated with cirrhosis (n = 35) or with inherited disease (n = 10). Nineteen (42.9%) had been transplanted previously. The patients' survival rate was 85% at 1 year and 82% at 3 years. Seven patients died within the first 3 months, due to severe polymicrobial infection. Two patients in the LK population (4.2%) developed acute rejection of the kidney graft compared to 24 of the 86 matched renal transplanted patients (32.6%). In parallel, acute liver rejection was observed in 14 cases (31.1%) in the LK population. The occurrence of acute rejection was not associated with panel-reactive lymphocytotoxic antibodies (n = 16), nor with positive cross-matches (n = 3). Four of the 45 patients (8.8%) subsequently developed chronic renal allograft rejection, and 16 cases of chronic hepatic dysfunction were noted (42.2%). In conclusion, the overall survival rate following combined liver kidney transplantation is acceptable, and LKT can be proposed to patients with kidney failure associated with liver dysfunction, primary oxaluria or amyloid neuropathy. The main cause of mortality in this population was severe infectious complications. The frequency of acute kidney rejection was lower than in single transplantation.     

Multigenic control of hepatic iron loading in a murine model of hemochromatosis

BACKGROUND & AIMS: Hereditary hemochromatosis is a common disorder of iron homeostasis characterized by increased dietary iron absorption and progressive iron accumulation, mainly in the liver. Most patients are homozygous for the C282Y mutation in the HFE gene. However, not all individuals carrying the hemochromatosis-predisposing genotype in the general population become iron loaded. Genetic modifiers have been shown to influence disease penetrance, but their number and chromosomal locations remain unknown, and their identification is hampered by complex interactions with environmental factors. To circumvent these difficulties, we used 2 strains of mice made deficient for the Hfe gene that strongly differ in their propensity to develop hepatic iron loading. METHODS: To localize the loci controlling hepatic iron loading in this murine model of hemochromatosis, we produced 1028 mice by an F2 intercross between the C57BL/6 and DBA/2 Hfe-deficient strains. We selected the 276 mice that contributed the most to the total linkage information for genotyping with 145 microsatellite markers. RESULTS: We mapped 4 modifier loci on chromosomes 7, 8, 11, and 12, with logarithm of odds scores of 14.47, 12.96, 6.04, and 6.72, respectively, in regions containing several genes recently shown to exert important roles in the regulation of iron metabolism. CONCLUSIONS: Our data provide a clear demonstration of the polygenic pattern of hepatic iron loading inheritance in Hfe-deficient mice. Examination of candidate genes residing at the loci identified in this study and genetic analysis of the syntenic chromosomal regions in humans may provide important insight into the heterogeneous disease presentation observed among HFE C282Y homozygotes.     

Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner

Deviation of the ambient temperature is one of the most ubiquitous stimuli that continuously affect mammals’ skin. Although the role of the warmth receptors in epidermal homeostasis (EH) was elucidated in recent years, the mystery of the keratinocyte mild-cold sensor remains unsolved. Here we report the cloning and characterization of a new functional epidermal isoform of the transient receptor potential M8 (TRPM8) mild-cold receptor, dubbed epidermal TRPM8 (eTRPM8), which is localized in the keratinocyte endoplasmic reticulum membrane and controls mitochondrial Ca²⁺ concentration ([Ca²⁺]_m). In turn, [Ca²⁺]_m modulates ATP and superoxide (O2•−) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and O2•− levels by cooling controls the balance between keratinocyte proliferation and differentiation. Finally, to ascertain eTRPM8’s role in EH in vivo we developed a new functional knockout mouse strain by deleting the pore domain of TRPM8 and demonstrated that eTRPM8 knockout impairs adaptation of the epidermis to low temperatures.The skin epidermis provides a protective barrier that guards the body against an uncongenial environment. Under the influence of a variety of ambient factors the skin epidermis undergoes continuous regeneration through so-called epidermal homeostasis (EH): the fine-tuning of the balance between proliferation, directional migration, differentiation, and death of keratinocytes. EH involves complex molecular and chemical pathways, regulating dynamic and continuous transition of keratinocytes from the proliferating state in the basal layer to the nonproliferating state in the suprabasal layer before the beginning of the differentiation in the stratum spinosum and stratum granulosum. The terminal differentiation step, characterized by keratinocyte death, transforms keratinocytes into corneocytes, which form the waterproof, mechanically resistant sheath of the stratum corneum (1).Deviation of the ambient temperature is one of the most important stimuli that constantly affect mammals’ skin. At ambient temperatures from +10 °C to +30 °C, the unprotected human skin temperature settles at mean steady-state values within the range of +24 °C to +33 °C, respectively (2). Temperature is perceived by thermoreceptors, the ion channels that belong to the transient receptor potential (TRP) superfamily (for review see ref. 3). Of these, TRPV1 and TRPV2 are activated by heat (above 42 °C and above 52 °C, respectively) (4), whereas TRPM8 and likely TRPA1 are activated by mild (5, 6) and noxious (7–9) cold, respectively. Heat-stimulated keratinocytes have been shown to secrete ATP (10) and, taking into account that purinergic receptors are expressed in keratinocytes (11), TRPV3 is involved in a paracrine heat-induced regulator of EH. Surprisingly, Grifford et al. recently reported that local heating of human skin does not result in accumulation of interstitial ATP (12), which refutes the significance of TRPV thermoreceptors in normal temperature-dependent EH. TRPV3 also was suggested to be important for corneocyte formation through Ca²⁺-dependent activation of cross-linking enzymes such as transglutaminase (13–15). Apart from heat-activated TRP, no successful attempt to elucidate the role of cold-sensitive TRP channels in EH has been reported yet. The range of thermoactivation of TRPM8 channel fits well with human unprotected skin temperature, +24 °C to +33 °C (5, 6). Apart from the observation that topical application of TRPM8 chemical agonists can improve epidermal regeneration (16), no solid evidence for the expression of functional TRPM8 in epidermal keratinocytes has been presented yet and no alterations in epidermal homeostasis have been reported in trpm8^−/− null mutant mice suppressing the full-length TRPM8 cold receptor (17, 18). However, suppression of the full-length TRPM8 expression does not necessarily affect expression of TRPM8 isoforms (19).Here we report the cloning and characterization of a new four-transmembrane domain epidermal isoform of the TRPM8 cold receptor channel, dubbed epidermal TRPM8 (eTRPM8). We demonstrate that eTRPM8 is localized and functions in the keratinocyte endoplasmic reticulum (ER) membrane where its activation within ER–mitochondria contact sites sustains mitochondrial Ca²⁺ uptake, thus affecting mitochondrial Ca²⁺ concentration ([Ca²⁺]_m). In turn, [Ca²⁺]_m modulates ATP and superoxide (O2•−) synthesis in a cold-dependent manner. We report that this fine-tuning of ATP and O2•− levels by cooling temperatures controls the balance between proliferation and differentiation of keratinocytes. Finally, to ascertain eTRPM8’s role in EH in vivo we developed a new functional knockout (KO) mouse line by deleting the active pore domain in all TRPM8 channel isoforms and demonstrated that eTRPM8 knockout impairs the epidermis adaptation to low temperatures and general skin homeostasis.     

Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors

It is becoming increasingly clear that signaling via G protein-coupled receptors is a diverse phenomenon involving receptor interaction with a variety of signaling partners. Despite this diversity, receptor ligands are commonly classified only according to their ability to modify G protein-dependent signaling. Here we show that beta2AR ligands like ICI118551 and propranolol, which are inverse agonists for Gs-stimulated adenylyl cyclase, induce partial agonist responses for the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1/2 thus behaving as dual efficacy ligands. ERK1/2 activation by dual efficacy ligands was not affected by ADP-ribosylation of Galphai and could be observed in S49-cyc- cells lacking Galphas indicating that, unlike the conventional agonist isoproterenol, these drugs induce ERK1/2 activation in a Gs/i-independent manner. In contrast, this activation was inhibited by a dominant negative mutant of beta-arrestin and was abolished in mouse embryonic fibroblasts lacking beta-arrestin 1 and 2. The role of beta-arrestin was further confirmed by showing that transfection of beta-arrestin 2 in these knockout cells restored ICI118551 promoted ERK1/2 activation. ICI118551 and propranolol also promoted beta-arrestin recruitment to the receptor. Taken together, these observations suggest that beta-arrestin recruitment is not an exclusive property of agonists, and that ligands classically classified as inverse agonists rely exclusively on beta-arrestin for their positive signaling activity. This phenomenon is not unique to beta2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited beta-arrestin and stimulated ERK1/2. These results point to a multistate model of receptor activation in which ligand-specific conformations are capable of differentially activating distinct signaling partners.     

Thoughts on the popularity of ICSI

PurposeIntracytoplasmic sperm injection (ICSI) is the most widely utilized assisted reproductive technique (ART) worldwide. In this feature, we review the early assisted fertilization attempts that eventually led to the development of ICSI, and discuss its current utilization in cases of male and non-male factor infertility.MethodsWe researched the literature related to the development, indications, and current use of ICSI, such as sperm structural abnormalities, male genetic indications, surgically retrieved sperm, high sperm chromatin fragmentation, oocyte dysmorphism, and preimplantation genetic testing (PGT). We also describe the potential future applications of ICSI.ResultsThis review summarizes the early micromanipulation techniques that led to the inception of ICSI. We also explore its current indications, including non-male factor infertility, where its use is more controversial. Finally, we consider the benefits of future advancements in reproductive biology that may incorporate ICSI, such as in vitro spermatogenesis, neogametogenesis, and heritable genome editing.ConclusionThe versatility, consistency, and reliability of ICSI have made it the most prevalently utilized ART procedure worldwide.