抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

Reported values in the literature on the number of cells in the body differ by orders of magnitude and are very seldom supported by any measurements or calculations. Here, we integrate the most up-to-date information on the number of human and bacterial cells in the body. We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·1013. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·1013 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.

/pdf/revised-estimates-for-the-number-of-human-and-bacteria-cells-4fb3y5elnx.pdf

Revised Estimates for the Number of Human and Bacteria Cells in the Body.

https://www.cell.com/molecular-cell/pdf/S1097-2765(08)00292-X.pdf

Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway

http://basicmed.med.ncku.edu.tw/admin/up_img/1007-2.pdf

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

CASE PRESENTATION A 2-year-old white toddler with unremarkable birth history presented with abdominal pain and jaundice associated with a diarrheal illness. His initial blood work showed elevated total bilirubin of 3 mg/dL, direct bilirubin of 2 mg/dL, aspartate amino transferase of 112 U/L, alanine amino transferase of 80 U/L, gamma glutamyl transferase of 128 U/L, alkaline phosphatase of 1077 U/L, and serum bile acids of 291 mmol/L. Coagulation profile, creatinine kinase, celiac panel, a-1-antitrypsin phenotype, copper, ceruloplasmin, and urine organic acids were unremarkable. He had no evidence of acetaminophen or alcohol toxicity. Infectious hepatitis workup including hepatitis A, B, C, E, Cytomegalovirus, Epstein-Barr virus, and Parvovirus serology were negative. Fasting lipid panel showed total cholesterol of 1090 mg/ dL, low density lipoprotein of 1031 mg/dL, and hypertriglyceridemia of 200 mg/dL. Emory Genetic Laboratory panel testing for 57 cholestasis-causing mutations was negative, including Alagille syndrome. For a period of 2 weeks he developed new-onset pruritus and his total bilirubin and direct bilirubin tripled (9.5 and 6.4 mg/ dL, respectively). Right upper quadrant ultrasound showed gallbladder sludge with nondilated common bile duct (CBD). A computerized tomography of the abdomen with oral and intravenous contrast was unremarkable. Percutaneous liver biopsy demonstrated cholestasis, biliary obstructive features, and acute cholangitis. Intravenous antibiotics were started for possible ascending cholangitis with no significant improvement. A magnetic resonance cholangiopancreatography confirmed the gall bladder sludge and showed dilatation of the common hepatic duct proximal to the cystic duct with abnormal narrowing of the CBD. An endoscopic retrograde cholangiopancreatography showed a long irregular high-grade stenosis of the CBD involving the cystic duct, an aberrant right posterior hepatic bile duct and dilated intrahepatic ducts with several filling defects. The CBD was too narrow to dilate or to stent (Fig. 1A). He had a percutaneous cholecystostomy tube placed that drained minimal bile. Due to persistent hyperbilirubinemia, he had repeat cholangiography and eventual placement of an external left hepatic duct percutaneous biliary drain that drained successfully. After 6 weeks, he underwent a laparoscopic cholecystectomy with partial resection of proximal CBD and hepaticoduodenostomy reconstruction. Diagnostic cholangiogram postresection demonstrated a patent residual common hepatic duct draining into the junction of the first and second portions of the duodenum. Pathologic evaluation of the CBD revealed marked mural thickening with a tumor diameter of 1.2 mm and no identifiable lumen (Fig. 1B). Histologic sections obtained from the gallbladder and CBD stricture showed aggregates of capillary sized blood vessels positive for endothelial cell markers CD31, CD34, and factor VIII-related antigen (Fig. 2). The Vascular proliferation was negative for glucose transporter 1 and Podoplanin (D2–40), which rules out, infantile hemangioma and locally aggressive Kaposi hemangioendothelioma, respectively. The Wilms tumor-1 (WT-1) immunostain was positive, and that makes a capillary vascular malformation less likely. Following the hepatico-duodenostomy, the bilirubin level normalized; however, aspartate amino transferase, alanine amino transferase, alkaline phosphatase and gamma glutamyl transferase remained slightly elevated. A cholangiogram via the percutaneous transhepatic biliary drain showed moderate dilatation of the left hepatic duct related to the drain and patent anastomosis. The biliary drain was successfully removed. His postoperative course was complicated by left hepatic duct stricture that required dilatation.

A Rare Case of Gallbladder and Common Bile Duct Benign Capillary Hemangioma in a Toddler.

PLACK syndrome: the penny dropped.

377 Type VII collagen (C7) expression and chimerism after bone marrow/cord blood transplantation (BMCBT) for severe generalized recessive dystrophic epidermolysis bullosa (RDEB)

continued this for 16 months. The second patient is a 46-year-old lady with multiple laBCCs on the forehead who was also irradiated for acne as a teenager. Her laBCCs resolved after taking vismodegib 150mg daily for 12 months. However, she experienced intractable cramps and nausea. She ceased vismodegib. These symptoms improved within 3 months. However, her laBCCs recurred. She then received sonidegib 200mg daily, and all laBCCs resolved within 6 months. She continues to have cramping and nausea but reports these are less severe than when on vismodegib. Faced with the decision of which agent to use in a patient with laBCC or mBCC there is little evidence to predict individual treatment response or tolerability. To our knowledge, there are no published studies comparing TEAEs in patients who have taken both drugs. In our two patients, changing hedgehog inhibitors led to a reduction in side effects allowing both to continue treatment. Both drugs were effective at treating their laBCCs. The PBS allows clinicians to swap patients from one hedgehog inhibitor to the other if efficacy is demonstrated but tolerability is not, just as psoriasis patients are able to switch between biologics. Given the paucity of other treatment options for laBCC and mBCC, we argue that clinicians should be aware of and utilise this provision. Further studies are justified to compare the efficacy and tolerability of vismodegib and sonidegib in this population.

John A. McGrath

Papers

A Rare Case of Gallbladder and Common Bile Duct Benign Capillary Hemangioma in a Toddler.

PLACK syndrome: the penny dropped.

377 Type VII collagen (C7) expression and chimerism after bone marrow/cord blood transplantation (BMCBT) for severe generalized recessive dystrophic epidermolysis bullosa (RDEB)

Pseudoporphyria induced by ultraviolet radiation.

A New Mutation and New Diagnostic Possibilities