Storylines of family medicine Ⅵ:ways of being—in the office with patients

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine,as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world.In‘Ⅵ:ways of being—in the office with patients’,authors address the following themes:‘Patient-centred care—cultivating deep listening skills’,‘Doctor as witness’,‘Words matter’,‘Understanding others—metaphor and its use in medicine’,‘Communicating with patients—making good use of time’,‘The patient-centred medical home—aspirations for the future’,‘Routine,ceremony or drama?’and‘The life course’.May readers better appreciate the nuances of patient care through these essays.

Multiple cells of origin in cholangiocarcinoma underlie biological,epidemiological and clinical heterogeneity

Recent histological and molecular characterization of cholangiocarcinoma(CCA) highlights the heterogeneity of this cancer that may emerge at different sites of the biliary tree and with different macroscopic or morphological features.Furthermore,different stem cell niches have been recently described in the liver and biliarytree,suggesting this as the basis of the heterogeneity of intrahepatic(IH)-and extrahepatic(EH)-CCAs,which are two largely different tumors from both biological and epidemiological points of view.The complexity of the organization of the liver stem cell compartments could underlie the CCA clinical-pathological heterogeneity and the criticisms in classifying primitive liver tumors.These recent advances highlight a possible new classification of CCAs based on cells of origin and this responds to the need of generating homogenous diagnostic,prognostic and,hopefully,therapeutic categories of IH-and EH-CCAs.

ANTAGONISTIC EFFECTS OF GRANULOCYTE DERIVED INHIBITORS AND CYTOKINES ON APOPTOSIS IN POLYMORPHONUCLEAR LEUKOCYTES

An extract (G-INH) made from mature human granulocytes freshly isolated from normai blood causes human neutrophils to undergo apoptosis in vitro as shown by morphologic changes and by the typical ladder pattern of small DNA fragments noted on agarose gel electrophoresis of isolated DNA. Apoptosis occurs in from 20% to 30% of neutrophils over 24 hours of culture in vitro and the addition of G-INH to the medium causes a dose-related increase in the incidence of apoptosis. Heating G-INH at 60t for 30 minutes does not destroy its capacity to induce apoptosis but GM-CSF, G-CSF, and to a lesser extent IL-1β, antagonize this action. IL-3 does not diminish G-INH induced apoptosis of neutrophils. Substances, released from, mature neutrophils may participate in regulating the survival of other neutrophils, particularly in sites where the cells are in close proximity as in the marrow. Self destruction of post-mitotic neutrophils in marrow may thus represent an-other level at which regulation of cell production

The new wave of p75 neurotrophin receptor targeted therapies

Neurotrophins have been recognized for decades for their beneficial effects on growth,survival,and maintenance in the central nervous system,all of which suggest potential therapeutic utility.Although understanding and harnessing the activity of neurotrophins has proven difficult,the past several years have seen significant strides in the development of deliverable therapies that modulate neurotrophin activity(Shen et al.,2019;Yang et al.,2020;Xie et al.,2021).These recent studies have primarily focused on the multifunctional p75 neurotrophin receptor(p75NTR)which is upregulated in central nervous system disease and injury,thus offering a unique target for intervention.

Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells

Wholly defined ex vivo expansion conditions for biliary tree stem cell(BTSC)organoids were established,consisting of a defined proliferative medium(DPM)used in combination with soft hyaluronan hydrogels.The DPM consisted of commercially available Kubota's Medium(KM),to which a set of small molecules,particular paracrine signals,and heparan sulfate(HS)were added.The small molecules used were DNA methyltransferase inhibitor(RG108),TGF-βType I receptor inhibitor(A83-01),adenylate cyclase activator(Forskolin),and L-type Ca2+channel agonist(Bay K8644).A key paracrine signal proved to be R-spondin 1(RSPO1),a secreted protein that activates Wnts.Soluble hyaluronans,0.05%sodium hyaluronate,were used with DPM to expand monolayer cultures.Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology[G*]of less than 100 Pa.The combination is called the BTSC-Expansion-Glycogel-System(BEX-gel system)for expanding BTSCs as a monolayer or as organoids.The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors.Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/-mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions.The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.

造血生长因子在人类CFU-GM和髓系白血病细胞系细胞凋亡中的调控作用(英文)

细胞凋亡是维系细胞群体数量相对衡定的重要的细胞移除机理。粒细胞源性抑制因子(G-INH)是一种源于成熟多形核粒细胞的提取物,具有对正常骨髓CFU-GM和HL-60细胞体外集落形成能力的抑制活性。加入高浓度造血生长因子(GM-CSF 50— 150U/ml,IL-3 50—75ng/ml)可逆转此种集落生长抑制且呈剂量-效应相关性。形态学、琼脂糖凝胶电泳以及DNA含量测定证实,G-INH(300μl/ml,温育3小时)具有诱导细胞凋亡活性。造血生长因子IL-1β(50U/ml),IL-3(25ng/ml)和GM-CSF(50U或5ng/ml)均可减轻G-INH的致细胞凋亡之作用。上述结果提示,G—INH与各种造血生长因子之间具有相互拮抗作用。该作用可能通过受体竞争性抑制或相关性受体结合所致的生物学下调节机制所介导。

Alzheimer病患者疾病感缺失与海马右尖下托淀粉样斑块密度有关

Background: Anosognosia is a common manifestation of Al zheimers disease. T here is an association between impaired awareness and frontal executive cogniti ve deficits. Anosognosia is also correlated with decreased metabolism in the rig ht hemisphere, particularly in frontal lobe regions. Objective: To investigate p athological correlates of anosognosia in Alzhe imers disease. Design: 41 subj ects followed longitudinally in the University of Pittsburgh memory disorders cl inic and with necropsy verified Alzheimers disease were divided into two group s, based on previous clinical assessment: +Aware (n = 23) and Aware (n = 18). A subset analysis matching sub jects for dementia severity using mini mental state examination scores was also carried out (13 +Aware; 13 Aware). Histopat hological data from necropsy brain tissue consisted of senile plaque (SP) and ne urofibrillary tangle (NFT) counts (regional density) from four different brain r egions in the right and left hemispheres: superior and middle frontal gyri (SMF) , superior temporal isocortex (ST), the prosubiculum of the hippocampus (PRO), a nd the entorhinal cortex (EC). Results: SP density was greater in the right PRO region of Aware subjects (F = 6.54, p = 0.015) than +Aware subjects. Signific ant differences between SP or NFT density were not observed in any other regions . In the subset analysis matching for dementia severity, SP density was again gr eater in the right PRO region of Aware subjects than in the other regions (F = 12.72, p = 0.002). Conclusions: Increased SP density in the right PRO region suggests that selective pathological involvement of th is area contributes to awareness deficits in Alzheimers disease. The putative role of the PRO in self appraisal may reflect its interconnections with other me dial temporal and prefrontal regions.

Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens

Recent data suggest that cystic fibrosis transmembrane conductance regulator(CFTR)gene alterations negatively impact male fertility beyond obstruction.We sought to compare gene alterations,sperm retrieval rates,and intracytoplasmic sperm injection(ICSI)outcomes among men with cystic fibrosis(CF)disease and congenital bilateral absence of the vas deferens(CBAVD)only.We retrospectively evaluated all men who underwent surgical sperm retrieval at two academic,high-volume andrology centers from 2010 to 2018.Only men with documented CFTR alterations and obstructive azoospermia from either CBAVD or CF were included.Differences between groups for CFTR abnormality,sperm retrieval,and ICSI outcomes were statistically analyzed.Overall,39 patients were included with 10 in the CF and 29 in the CBAVD groups.Surgical sperm retrieval rates were significantly lower in the CF group for sperm concentration(14.8×10^(6)ml^(-1)vs 61.4×10^(6)ml^(−1),P=0.02)and total motile sperm count(2.9 million vs 11.4 million,P=0.01).This difference was only predicted by homozygous delta F508 CFTR mutations(P<0.05).The CF group also demonstrated a significantly higher rate of rescue testicular sperm extraction(70.0%vs 27.6%,P<0.03)and lower fertilization rate with ICSI(32.5%vs 68.9%,P<0.01).In conclusion,those with CF demonstrated lower sperm quality,greater difficulty with sperm retrieval,and worse ICSI outcomes compared with CBAVD-only patients.Homozygous delta F508 CFTR mutations appear to significantly impair spermatogenesis and sperm function.

Liver cell therapies:cellular sources and grafting strategies

The liver has a complex cellular composition and a remarkable regenerative capacity.The primary cell types in the liver are two parenchymal cell populations,hepatocytes and cholangiocytes,that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells,endothelia and various hemopoietic cell populations.The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates,the extracellular matrix,working synergistically with soluble paracrine and systemic signals.In recent years,with the rapid development of genetic sequencing technologies,research on the liver’s cellular composition and its regulatory mechanisms during various conditions has been extensively explored.Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases,offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation.This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair.Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

J Clin Pharm Ther：外用聚维酮碘溶液能够导致血糖测量值高估

血液中的糖分称为血糖，绝大多数情况下都是葡萄糖（英文简写Glu）。体内各组织细胞活动所需的能量大部分来自葡萄糖，所以血糖必须保持一定的水平才能维持体内各器官和组织的需要。根据一项病例报告，使用外用碘溶液能够导致血糖测量值高估。相关研究结果在线发表在Journal of Clinincal Pharmacy and Therapeutics期刊上。论文标题为＂Probable glucometer interference caused by topical iodine solution test site preparation＂。