Lipolysis supports bone formation by providing osteoblasts with endogenous fatty acid substrates to maintain bioenergetic status

Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.

Cardiac Manifestations with Chemotherapeutic Agents: 5 Fluorouracil-Induced Coronary Artery Vasospasm

5-fluorouracil (5-FU) is a fluorinated, pyrimidine analog, antineoplastic agent that is used in the treatment of several solid organ cancers. Cardiotoxicity is uncommon but life-threatening manifestations such as myocardial infarction may manifest owing to 5-FU-induced coronary artery spasm. Administering smaller doses of the drug, more frequently than not, decreases the risk of cardiotoxicity compared to large doses or with continuous infusions. We present a case of ST-segment elevation in a patient without known coronary artery disease who had presented following continuous 5-FU infusion. Coronary angiogram confirmed absence of coronary artery disease and intravenous calcium channel blockers administration was commensurate with the patient’s improvement in symptoms. We discuss the literature on 5-FU and its association with coronary artery spasm, and also briefly review chemotherapy-induced cardiotoxicities to help better prepare internists and other primary health care providers to face similar challenges, particularly of the uncommon but potentially life-threatening manifestations.

Generation of iPS cells using defined factors linked via the self-cleaving 2A sequences in a single open reading frame

Generation of induced pluripotent stem （iPS） cells from somatic cells has been achieved successfully by simultaneous viral transduction of defined reprogramming transcription factors （TFs）. However, the process requires multiple viral vectors for gene delivery. As a result, generated iPS cells harbor numerous viral integration sites in their genomes. This can increase the probability of gene mutagenesis and genomic instability, and present significant barriers to both research and clinical application studies of iPS cells. In this paper, we present a simple lentivirus reprogramming system in which defined factors are fused in-frame into a single open reading frame （ORF） via self-cleaving 2A sequences. A GFP marker is placed downstream of the transgene to enable tracking of transgene expression. We demonstrate that this polycistronic expression system efficiently generates iPS cells. The generated iPS cells have normal karyotypes and are similar to mouse embryonic stem cells in morphology and gene expression. Moreover, they can differentiate into cell types of the three embryonic germ layers in both in vitro and in vivo assays. Remarkably, most of these iPS cells only harbor a single copy of viral vector. This system provides a valuable tool for generation of iPS cells, and our data suggest that the balance of expression of transduced reprogramming TFs in each cell is essential for the reprogramming process. More importantly, when delivered by non-integrating gene-delivery systems, this re-engineered single ORF will facilitate efficient generation of human iPS cells free of genetic modifications.

Use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction

The management options for ureteral obstruction are diverse, including retrograde ureteral stent insertion or antegrade nephrostomy placement, with or without eventual antegrade stent insertion. There is currently no consensus on the ideal treatment or treatment pathway for ureteral obstruction owing, in part, to the varied etiologies of obstruction and diversity of institutional practices. Additionally, different clinicians such as internists, urologists, oncologists and radiologists are often involved in the care of patients with ureteral obstruction and may have differing opinions concerning the best management strategy. The purpose of this manuscript was to review available literature that compares percutaneous nephrostomy placement vs ureteral stenting in the management of ureteral obstruction from both benign and malignant etiologies.

IPCEA全科医学教学病例——肠易激综合征误诊知多少

目的这篇文章证明了运用一个广泛的鉴别诊断所带来的好处以及确定最可能的诊断的适用方法。方法运用临床病例呈现、结果讨论和总结的方法。结果这个临床病例呈现是为需要提高他们的临床技能的中国内科实习医生正在开展的教学项目的一部分。这些积极地进行实践的内科医生学生们预先评价他们的病人,并以书面的形式把这个病例带到课堂,这个病人也来到课堂重新进行询问和测试。这名实习医生的导师带领其他参加的学生一起进行病例讨论。针对诊断的构成、病史因素、测试和测试结果进行讨论来形成最为可能的病因的排名。另外进行深入的综合征,即肠易激综合征(IBS)讨论来呈现出如何确定最为可能的病因的过程。结论这些技能和方法是讲解医学诊断过程所用的有效适用的教学模式,有助于执业医师获得更为综合和准确的诊断结果。对提高一个合格医生的满意度并实现帮助病人的这个终极目标都有很大帮助。

Bone Remodeling and Energy Metabolism:New Perspectives

Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.

Metabolic programming determines the lineage-differentiation fate of murine bone marrow stromal progenitor cells

Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate.To determine the molecular mechanisms,we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors(BMSCs^adipo and BMSC^sosteo,respectively)under basal and adipogenic culture conditions.At baseline,BMSCs^adipo,and BMSCs^osteo exhibit a distinct metabolic program evidenced by the presence of specific global gene expression,cellular bioenergetics,and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs^osteo versus oxidative phosphorylation in BMSCs^adipo.To test the flexibility of the metabolic program,we treated BMSCsadipo with parathyroid hormone,S961(an inhibitor of insulin signaling)and oligomycin(an inhibitor of oxidative phosphorylation).The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic differentiation.Similarly,12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors,enhanced adipocyte differentiation and insulin signaling in cultured BMSCs.Our data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.

A peptide containing the receptor binding site of insulin-like growth factor binding protein-2 enhances bone mass in ovariectomized rats

Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.

肾病综合征表现的局灶性节段性肾小球硬化的远期预后分析(英文)

本文将针对25年来治疗局灶性节段性肾小球硬化的一项区域性儿童肾脏病协作计划进行系统回顾。所有患儿经肾穿刺诊断为局灶性节段性肾小球硬化,其中大部分为美国黑人患儿,与之前报道的患同样疾病以白人为主体的患儿比较,他们的临床特点和远期预后均有不同。由于亚洲和非洲的肾病患儿局灶性节段性肾小球硬化的发生率均较高,因此中国患儿可能在疾病的临床特征、对治疗的反应和远期预后等方面与本文所讨论的美国黑人患儿类似。

Tuberculosis Otitis Media with Disseminated Tuberculosis in a Pregnant Female

Background: Tuberculosis remains a public health problem worldwide, and tuberculosis in pregnancy in particular can have effects on both mother and infant. Findings: We report a case of a 22- year-old female presenting in preterm labor at 32 weeks gestation. Her pregnancy had been complicated by hearing loss and weight loss, and at the time of delivery, she was diagnosed with tuberculous otitis media and disseminated tuberculosis. Tuberculous otitis media is a rare form of tuberculosis disease, and in this case, had consequences for mother and infant. Conclusions: Importance of suspicion for tuberculosis disease in patients presenting with atypical symptoms but epidemiologic history is emphasized.

Macrophage migration inhibitory factor inhibits BMP-4 induced apoptosis

Non-canonical bone morphogenic protein (BMP) pathway signaling plays a critical role during embryonic neurogenesis, inducing apoptosis and eliminating an excess of neural progenitor cells, in preparation for the population of the neural stem cell niches. Our previous work discovered that non-canonical BMP signaling also induced the expression of the anti-apoptotic cytokine macrophage migration inhibitory factor (MIF). Because there are residual neural progenitors that escape BMP induced apoptosis, we believed the expression of MIF could be used to counter this specific type of developmental apoptosis. In vitro studies using P19 cells and ex vivo studies using E13 neural progenitor from wild type and mif-/-mice revealed that overexpression of mif was able to counteract BMP induced apoptosis, while in contrast ablation of mif resulted in a dramatic increase in apoptosis. Despite this finding, it is interesting to note that mif-/-mice, while presenting an overall increase in apoptosis are viable, ablation of mif expression in zebrafish and frog are embryonic lethal, suggesting a redundant or non-critical role of MIF in the developing mammalian embryo.

Olig1 and Olig2 promotes oligodendrocyte differentiation of neural stem cells in adult mice injured by EAE

Investigating neural stem cell plasticity in the hippo-campal niche, we demonstrate that retroviral forced expression of Mash1 (Mammalian Achaete-Scute Homolog 1), Olig1(Oligodendrocyte transcription factor 1), and Olig2 (Oligodendrocyte transcription factor 2) genes, transcription factors involved in enhanced oligodendrogenesis, can contribute to directing the differentiation of adult subventricular zone neural stem cells to functional oligodendrocytes. We found that Mash1, Olig1 and Olig2 all induced oligodendrocyte differentiation. However, Olig1 and Olig2 induction resulted in an elevated number of generated oligoden-drocytes without a significant production of other cell lineages, unlike Mash1. These newly differentiated cells are also capable of migration and possible myelination, showing that targeting oligodendrocyte production and possible remyelination is a viable therapeutic strategy for restoration of neuronal function.

A Case of Posttraumatic Cervical Dystonia Treated with OnabotulinumtoxinA

Cervical dystonia (CD) is a condition that typically presents with cervical muscle spasm, producing head tilt and cervical rotation. CD is most often idiopathic, however, in a small number of patients, CD occurs within one day to one year after mild to severe trauma. This type of CD is further classified as posttraumatic CD. OnabotulinumtoxinA (Botox) injections are considered to be a controversial treatment for posttraumatic CD and have produced variable result. This report describes the case of a 32-year-old female presenting with a two year history of posttraumatic CD and associated head, neck, and shoulder pain after obtaining a severe head injury during a motorcycle accident. OnabotulinumtoxinA was used to successfully treat her posttraumatic CD muscle spasms and associated chronic pain. Three months after her first and second ONA treatments, the patient reported at least 50% improvement in her overall pain symptoms and a noticeable reduction in cervical paraspinal muscle spasms.

IgA肾病患儿治疗的研究进展

1968年IgA肾病首次被描述，最初称为Berger病。先证者为法国患儿，表现为急性上呼吸道感染数天后出现无症状肉眼血尿。肾活检显示系膜区显著扩大、IgA沉积，因此被命名为IgA肾病。此后40年临床治疗实践中，对该病自然病程了解逐渐增多，但对其发病机制知之甚少。20世纪80年代，D，Amico和其他学者已经认识到IgA肾病是世界上最常见的肾小球肾炎。因此，Julian等指出该病对1％以上的人口有影响。

Klotho in Osx+-mesenchymal progenitors exerts pro-osteogenic and anti-inflammatory effects during mandibular alveolar bone formation and repair

Maxillofacial bone defects are commonly seen in clinical practice.A clearer understanding of the regulatory network directing maxillofacial bone formation will promote the development of novel therapeutic approaches for bone regeneration.The fibroblast growth factor(FGF)signalling pathway is critical for the development of maxillofacial bone.Klotho,a type I transmembrane protein,is an important components of FGF receptor complexes.Recent studies have reported the presence of Klotho expression in bone.However,the role of Klotho in cranioskeletal development and repair remains unknown.Here,we use a genetic strategy to report that deletion of Klotho in Osx-positive mesenchymal progenitors leads to a significant reduction in osteogenesis under physiological and pathological conditions.Klotho-deficient mensenchymal progenitors also suppress osteoclastogenesis in vitro and in vivo.Under conditions of inflammation and trauma-induced bone loss,we find that Klotho exerts an inhibitory function on inflammation-induced TNFR signaling by attenuating Rankl expression.More importantly,we show for the first time that Klotho is present in human alveolar bone,with a distinct expression pattern under both normal and pathological conditions.In summary,our results identify the mechanism whereby Klotho expressed in Osx+-mensenchymal progenitors controls osteoblast differentiation and osteoclastogenesis during mandibular alveolar bone formation and repair.Klotho-mediated signaling is an important component of alveolar bone remodeling and regeneration.It may also be a target for future therapeutics.

Protocoled thrombolytic therapy for frostbite improves phalangeal salvage rates

Background:Frostbite is a cold injury that has the potential to cause considerable morbidity and long-term disability.Despite the complexity of these patients,diagnostic and treatment practices lack standardization.Thrombolytic therapy has emerged as a promising treatment modality,demonstrating impressive digit salvage rates.We review our experience with thrombolytic therapy for severe upper extremity frostbite.Methods:Retrospective data on all frostbite patients evaluated at our institution from December 2017 to March 2018 was collected.A subgroup of patients with severe frostbite treated with intraarterial thrombolytic therapy(IATT)were analysed.Results:Of the 17 frostbite patients treated at our institution,14(82%)were male and the median age was 31(range:19–73).Substance misuse was involved in a majority of the cases(58.8%).Five(29.4%)patients with severe frostbite met inclusion criteria for IATT and the remaining patients were treated conservatively.Angiography demonstrated a 74.5%improvement in perfusion after tissue plasminogen activator thrombolysis.When comparing phalanges at risk on initial angiography to phalanges undergoing amputation,the phalangeal salvage rate was 83.3%and the digit salvage rate was 80%.Complications associated with IATT included groin hematoma,pseudoaneurysm and retroperitoneal hematoma.Conclusions:Thrombolytic therapy has the potential to greatly improve limb salvage and functional recovery after severe frostbite when treated at an institution that can offer comprehensive,protocoled thrombolytic therapy.A multi-center prospective study is warranted to elucidate the optimal treatment strategy in severe frostbite.

Aberrant expression of Twist1 in diseased articular cartilage and a potential role in the modulation of osteoarthritis severity

The bHLH transcription factor Twist1 has emerged as a negative regulator of chondrogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chondrocytes.However,its role in articular cartilage remains obscure.Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes,the distribution of Twist1 proteins in normal versus OA human articular cartilage,and its role in modulating OA development in mice.High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features.The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro.In normal human articular cartilage,Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones.However,our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage.Moreover,Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples.To assess the role of Twist1 in OA pathophysiology,we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus.At 12 weeks post-surgery,micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice.Collectively,the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration.

围手术期输注红细胞可降低心脏手术术后远期存活率

背景输注红细胞（RBC）与心脏手术后死亡率升高有关。我们分析了在住院期间接受了1或2个单位RBC输注的心脏手术患者的长期生存情况。方法将2001年至2004年期间9079例，在新英格兰北部地区8个医疗中心中接受了冠状动脉旁路移植术、瓣膜手术或同时进行了冠状动脉旁路移植术和瓣膜手术的患者纳入本研究。研究将纳入地区与2006年6月30日社会保障署死亡档案确定的死亡率进行概率性配对。调整的风险比采用Cox比例风险和倾向评分法进行计算。结果36％的患者（n=3254）接受过1或2个单位的RBC。43％的RBCs是在手术中被输注的，分别有56％和1％的RBCs是在手术后和手术前输注的。输血的患者更可能是贫血、高龄、体表面积小、女性和同时患多种疾病的患者。那些在心脏手术住院期间接受了1或2个单位RBCs的患者的存活率显著低于未接受过RBCs的患者（P〈0．001）。调整了患者和疾病特征之后，接受1或2个单位RBCs仍使远期死亡风险提高16％（调整的风险比=1．16，95％CI：1．01—1．34，P=0．035）。结论输注1或2个单位的RBCs可使心脏手术术后存活率降低的风险提高16％。

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID- 19 pandemic

Background During the COVID-19 pandemic,decreased volumes of stroke admissions and mechanical thrombectomy were reported.The study’s objective was to examine whether subarachnoid haemorrhage(SAH)hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines.Methods We conducted a cross-sectional,retrospective,observational study across 6 continents,37 countries and 140 comprehensive stroke centres.Patients with the diagnosis of SAH,aneurysmal SAH,ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases,10th Revision,codes.The 3-month cumulative volume,monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before(1 year and immediately before)and during the pandemic,defined as 1 March-31 May 2020.The prior 1-year control period(1 March-31 May 2019)was obtained to account for seasonal variation.Findings There was a significant decline in SAH hospitalisations,with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic,representing a relative decline of 22.5%(95%CI−24.3%to−20.7%,p<0.0001).Embolisation of ruptured aneurysms declined with 1170-1035 procedures,respectively,representing an 11.5%(95%CI−13.5%to−9.8%,p=0.002)relative drop.Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations,a 24.9%relative decline(95%CI−28.0%to−22.1%,p<0.0001).A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1%(95%CI 32.3%to 50.6%,p=0.008)despite a decrease in SAH admissions in this tertile.Interpretation There was a relative decrease in the volume of SAH hospitalisations,aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic.These findings in SAH are consistent with a decrease in other emergencies,such as stroke and myocardial infarction.