Portal hypertension(PH)is a major complication of chronic liver disease,often leading to serious clinical consequences such as variceal bleeding,ascites,and splenomegaly.The current gold standard for PH diagnosis,name...Portal hypertension(PH)is a major complication of chronic liver disease,often leading to serious clinical consequences such as variceal bleeding,ascites,and splenomegaly.The current gold standard for PH diagnosis,namely,hepatic venous pressure gradient measurement,is invasive and not widely available.Transient elastography has emerged as a non-invasive alternative for assessing liver stiffness(LS),and recent studies have highlighted the potential role of splenic stiffness(SS)in evaluating PH severity.This narrative review summarizes the available evidence on the utility of splenic transient elastography in assessing PH.We evaluated its diagnostic accuracy,technical challenges,and clinical applications,particularly in distinguishing between cirrhotic PH(CPH)and noncirrhotic PH(NCPH).A comprehensive literature search was conducted using the PubMed database,focusing on studies that assess splenic elastography in the diagnosis and prognosis of PH.This review compares splenic elastography with other non-invasive imaging modalities,including MR elastography and shearwave elastography.Additionally,we examined the role of SS using elastography in predicting the presence of esophageal varices and its potential impact on reducing the need for endoscopic screening.Studies have demonstrated that splenic elastography correlates well with PH severity,with cut-off values ranging between 45 kPa and 50 kPa for significant PH detection.Splenic elastography,when combined with platelet count and LS measurements,improves diagnostic accuracy and risk stratification for the occurrence of variceal bleeding.Despite its clinical promise,technical challenges such as patient positioning,body habitus,and probe selection remain key limitations.Notably,splenic elastography may be particularly useful in diagnosing NCPH,where LS remains normal but PH is present.Splenic transient elastography is a valuable adjunct in the non-invasive assessment of PH.Its ability to predict varices,differentiate between CPH and NCPH,and reduce unnecessary endoscopies suggests that it should be incorporated into routine hepatology practice.Future research should focus on refining SS cut-offs,evaluating its cost-effectiveness,and integrating splenic elastography into clinical guidelines for PH management.展开更多
With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis...With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.展开更多
Postural tachycardia syndrome(POTS)is a chronic autonomic disorder characterized by excessive heart rate elevation upon standing or head-up tilt,in the absence of orthostatic hypotension.This debilitating condition af...Postural tachycardia syndrome(POTS)is a chronic autonomic disorder characterized by excessive heart rate elevation upon standing or head-up tilt,in the absence of orthostatic hypotension.This debilitating condition affects primarily young to middle-aged individuals,particularly women,and substantially influences quality of life.The main present-ing symptoms are lightheadedness,palpitations,exercise intolerance,and cognitive impairment.POTS is of particular importance to cardiologists,given its prominent cardiovascular symptoms.The diagnostic criteria for POTS include a sustained heart rate increase of more than 30 beats per minute upon standing or head-up tilt;symptoms of orthostatic intolerance lasting at least 3 months;and exclusion of other causes.The exact etiology of POTS is unknown,but mul-tiple possible etiologies leading to a similar clinical phenotype have been proposed.Early intervention and appropri-ate management can improve symptoms.Treatment strategies include lifestyle modifications,pharmacotherapy,and tailored conditioning programs.Non-pharmacologic options are the first line treatment.Prognosis varies widely:POTS can be a temporary condition for some individuals but a chronic and debilitating condition for others.Further research is necessary to elucidate the pathophysiology and optimize treatment strategies for this condition.展开更多
Serum levels of cartilage oligomeric matrix protein(COMP) has been presented as a biomarker of liver fibrosis in several cross-sectional studies. COMP is also an essential mediator in carcinoma development and has als...Serum levels of cartilage oligomeric matrix protein(COMP) has been presented as a biomarker of liver fibrosis in several cross-sectional studies. COMP is also an essential mediator in carcinoma development and has also been associated with hepatocellular carcinoma. We present a prospective analysis of this biomarker in38 patients with chronic hepatitis C who were subject to eradication therapy with direct acting antivirals. We confirm previous studies associating COMP elevation with liver cirrhosis. We also show how viral levels are correlated with COMP at baseline. In our prospective analysis, we report that successful eradication of hepatitis C results in improvement in liver stiffness and laboratory liver function tests at 1 year follow-up. In contrast, median COMP-levels remain unchanged during the study period. We conclude that the biomarker potential of COMP in the prospective evaluation of liver diseases, remains to be elucidated.展开更多
Objective: Hyponatremia is the most common electrolyte imbalance. The initial treatment decision is based on clinical evaluation of patient volume status but an accurate assessment is difficult, particularly different...Objective: Hyponatremia is the most common electrolyte imbalance. The initial treatment decision is based on clinical evaluation of patient volume status but an accurate assessment is difficult, particularly differentiating mild hypovolemia from euvolemia. The aim of this study is to examine if biomarkers are valuable in the early determination of volume status and SIADH diagnosis. Methods: Blood samples were collected from an unselected patient population at entry to the Emergency Department. If the plasma sodium level (P-Na) was ≤125 mmol/L, the sample was frozen for further analysis. Mid-regional pro-atrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), C-terminal prepro-vasopressin (copeptin), pro-endothelin-1 (proET-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were analysed. A comprehensive assessment of volume status and underlying causes was made after discharge blinded for biomarker results. Results: A total of 81 patients were included. A well substa ntiated volemic state (hypo/eu/hypervolemia) was established in 72 patients (mean age 76 years, 65% women, median P-Na 119 mmol/L). A significant association was observed between MR-proANP levels and volemic state (p = 0.0001). Data was specifically analysed with respect to distinguishing hypo- from euvolemia (n = 59) using logistic regression. In a crude analysis, MR-proANP was significantly related to euvolemia (OR: 2.54 per SD of MR-proANP, 95% CI 1.32 - 4.86, p = 0.005) and remained so after the multivariate backward elimination model (OR: 2.45 per SD of MRproANP, 95% CI 1.22 - 4.91, p = 0.012.), whereas the other studied biomarkers were not. Copeptin levels were not associated with a diagnosis of SIADH. Conclusions: MR-proANP may be of value in early determination of volume status in hyponatremic patients.展开更多
Background:Parents of children with complex right ventricular outflow tract(RVOT)anomalies are confronted with their child’s need for heart surgery early in life and repeated reoperations later on.Preoperative assess...Background:Parents of children with complex right ventricular outflow tract(RVOT)anomalies are confronted with their child’s need for heart surgery early in life and repeated reoperations later on.Preoperative assessment needs to be performed whenever an indication for reoperation is suspected.The aim was to illuminate the experiences of parents of children diagnosed with RVOT anomalies,in particular,how they experience their child’s heart disease and everyday life during the assessment and after the decision on whether to perform a reoperation.Method:Individual interviews(n=27)were conducted with nine parents on three occasions between 2014 and 2016 and analyzed using reflexive thematic analysis.Results:The analysis resulted in the following five main coexisting themes:The heart surgery keeps my child alive illuminates parents’experiences during and after the assessment and emphasizes that heart surgery,although dreaded,is central for their child’s survival;Everyday struggles illuminates the different struggles parents had to face to ensure that their child would be in the best possible condition;the remaining three themes,Unconditional love,Trust in life,and Togetherness,illuminate the ways in which the parents gained inner strength and confidence in their everyday lives.Conclusion:Although the parents were grateful for the assessment and had learned to navigate among the fears it aroused,they experienced several distressing situations during the assessment process that should be addressed.By inviting both the parents and their child to participate in the child’s care,individualized support can take into account the needs of both parents and child.展开更多
BACKGROUND The enteric nervous system(ENS)is situated along the entire gastrointestinal tract and is divided into myenteric and submucosal plexuses in the small and large intestines.The ENS consists of neurons,glial c...BACKGROUND The enteric nervous system(ENS)is situated along the entire gastrointestinal tract and is divided into myenteric and submucosal plexuses in the small and large intestines.The ENS consists of neurons,glial cells,and nerves assembled into ganglia,surrounded by telocytes,interstitial cells of Cajal,and connective tissue.Owing to the complex spatial organization of several interconnections with nerve fascicles,the ENS is difficult to examine in conventional histological sections of 3-5μm.AIM To examine human ileum full-thickness biopsies using X-ray phase-contrast nanotomography without prior staining to visualize the ENS.METHODS Six patients were diagnosed with gastrointestinal dysmotility and neuropathy based on routine clinical and histopathological examinations.As controls,fullthickness biopsies were collected from healthy resection ileal regions after hemicolectomy for right colon malignancy.From the paraffin blocks,4-μm thick sections were prepared and stained with hematoxylin and eosin for localization of the myenteric ganglia under a light microscope.A 1-mm punch biopsy(up to 1 cm in length)centered on the myenteric plexus was taken and placed into a Kapton®tube for mounting in the subsequent investigation.X-ray phase-contrast tomography was performed using two custom-designed laboratory setups with micrometer resolution for overview scanning.Subsequently,selected regions of interest were scanned at a synchrotron-based end-station,and high-resolution slices were reported.In total,more than 6000 virtual slices were analyzed from nine samples.RESULTS In the overview scans,the general architecture and quality of the samples were studied,and the myenteric plexus was localized.High-resolution scans revealed details,including the ganglia,interganglional nerve fascicles,and surrounding tissue.The ganglia were irregular in shape and contained neurons and glial cells.Spindle-shaped cells with very thin cellular projections could be observed on the surface of the ganglia,which appeared to build a network.In the patients,there were no alterations in the general architecture of the myenteric ganglia.Nevertheless,several pathological changes were observed,including vacuolar degeneration,autophagic activity,the appearance of sequestosomes,chromatolysis,and apoptosis.Furthermore,possible expulsion of pyknotic neurons and defects in the covering cellular network could be observed in serial slices.These changes partly corresponded to previous light microscopy findings.CONCLUSION The analysis of serial virtual slices could provide new information that cannot be obtained by classical light microscopy.The advantages,disadvantages,and future possibilities of this method are also discussed.展开更多
Hyponatremia is a severe electrolyte disturbance associated with substantial morbidity and mortality. It often poses a diagnostic and therapeutic challenge. Accurate assessment of patient fluid-volume status is centra...Hyponatremia is a severe electrolyte disturbance associated with substantial morbidity and mortality. It often poses a diagnostic and therapeutic challenge. Accurate assessment of patient fluid-volume status is central to effective management. This pilot study aimed to evaluate the usefulness of the Cheetah NICOM bioreactance system and apelin in early differentiation between hypo- and euvolemia in patients with severe hyponatremia. <strong>Methods:</strong> Patients > 50 years of age with a serum sodium ≤ 125 mmol/L were eligible for inclusion after written informed consent. Blood- and urine analyses of cardiovascular load (NT-proBNP), osmotic stress (copeptin, apelin, osmolality, sodium), mineralocorticoid status (aldosterone, renin) and sympathetic activity (methoxycathecholamines) were analysed at baseline and after isotonic sodium chloride infusion. Bedside bioreactance examination was used to visualise parameters, including stroke volume before and after passive leg raise test. Classification of volume status was made retrospectively blinded for biomarker and bioreactance results. <strong>Results:</strong> 8 patients (4 hypovolemic and 4 euvolemic), 79 years old, median plasma sodium 120 mmol/L were included. At the Emergency Department volume status was misclassified in all hypo- and in 2 of 4 euvolemic patients. Apelin was significantly higher in hypovolemic patients ((299 vs. 175 ng/ml), p = 0.021). All hypovolemic, but none of the euvolemic, patients had a level above 250 ng/ml. Copeptin did not differ between groups. All patients in the hypovolemic group increased their stroke volume after passive leg raise. <strong>Conclusions:</strong> Apelin seems to be a promising future biomarker in the early management of severe hyponatremia. Bioreactance measurements may offer a supplement to bedside evaluation of volume status.展开更多
Background: Several studies have shown that persons with schizophrenia (PWS) suffer from severely reduced quality of life (QoL). Impaired social functioning is a defining characteristic of schizophrenia (SZ) and socia...Background: Several studies have shown that persons with schizophrenia (PWS) suffer from severely reduced quality of life (QoL). Impaired social functioning is a defining characteristic of schizophrenia (SZ) and social cognition deficits affect interpersonal relations and outcomes such as independent living, vocational functioning and employment status. Some studies have demonstrated important socio-cultural aspects of SZ, for instance by examining experiences of SZ in different developing countries and among minority groups in the Western world. The socio-cultural context is central to understanding patients’ experiences in any society, however. Using an anthropological approach, we use qualitative research methods to examine patient perspectives on SZ. Sampling and Methods: In-depth qualitative interviews are carried out with SZ patients in France, the UK and the USA representing diversity in Western mental health systems. Results: To the participants, the most important QoL aspects are close relations and support from loved ones, a safe home and comfort zone, and meaningful daily activities. Normalisation and independence act as central themes to patients’ QoL and hopes for social integration. The participants need a buffer zone consisting of social relations, a home and daily occupation that is flexible and may balance issues of equality/inequality, abnormality/normality, and dependence/independence. Conclusion: By using participatory methods, PWS may be involved in shaping their own treatment and recovery plans based on what is subjectively meaningful and beneficial to their mental health. QoL and functioning are closely linked to the socio-cultural context in which health care structures go hand in hand with health care cultures that shape patients’ expectations and preferences.展开更多
Problem gambling is over-represented in patients treated for substance use disorders, but substance-specific prevalence of problem gambling is rarely reported. In specialized addiction treatment facilities for opioid ...Problem gambling is over-represented in patients treated for substance use disorders, but substance-specific prevalence of problem gambling is rarely reported. In specialized addiction treatment facilities for opioid maintenance treatment and for alcohol and prescription drug dependence, respectively, 129 patients were screened for problem gambling using the NODS-CLiP. The lifetime prevalence of problem gambling was markedly higher in opioid maintenance treatment (61 percent) than in alcohol and prescription drug dependence treatment (11 percent, p < 0.001). When controlling for gender and age, problem gambling remained significantly associated with opioid maintenance treatment. The present study demonstrated a very high prevalence of lifetime problem gambling in opioid maintenance treatment patients. This calls for active screening for problem gambling in substance use disorder patients, and mainly in treatment for opioid dependence.展开更多
Background: Several studies analyze how surgical delay affects patients with hip fracture. The aim of this study was to identify the causes of surgical delay and demographic characteristics in patients with hip fractu...Background: Several studies analyze how surgical delay affects patients with hip fracture. The aim of this study was to identify the causes of surgical delay and demographic characteristics in patients with hip fracture who had delays longer than 24 hours from admission to hospital. Methods: Quantitative retrospective register study of 484 patients was consecutively included during the period November 1, 2010 and October 31, 2011 in the University Hospital in Lund (Sweden). Results: A frequency of 29.4% had a surgical delay longer than 24 hours. The main reasons for delays to surgery were lack of theatre facilities (54%), medical unstable patient (16%) and anticoagulant treatment (10%). Of all patients, 69% (n = 332) were women and 31% (n = 151) were men. The mean age for women were 83.6 (CI 83-85) vs. 79 (CI 77-81) for men, respectively. The most common type of hip fracture was displaced cervical hip fracture (39%, n = 188) with a majority of fractures in male patients. In total, women suffered hip fractures to a greater extent than men (69% vs. 31%, p = 0.016), but no relationship was found with respect to the fracture type and age (p = 0.358). Conclusion: The main result demonstrated that delays longer than 24 hours were due to lack of theatre facilities. Further researches have to be done in order to investigate whether lack of theatre facilities depends on improper operation planning and/or on lack of medical staff.展开更多
Purpose: To evaluate the impact of field strength and respiratory motion control on diffusion-weighted MR imaging (DWI) of the liver at 1.5 and 3 T. Material and Methods: Three DWI sequences using seven b-values from ...Purpose: To evaluate the impact of field strength and respiratory motion control on diffusion-weighted MR imaging (DWI) of the liver at 1.5 and 3 T. Material and Methods: Three DWI sequences using seven b-values from 20 - 400 s/mm2 were designed with identical parameters but with different handling of respiratory motion [respiratory triggered (RT), free breathing (FB), breath hold (BH)] on 3 T and 1.5 T. Thirteen volunteers were examined at a 3 T and six of them also at a 1.5 T magnet. DW images were analyzed quantitatively and qualitatively. Regions of interest were placed in cranial, middle and caudal parts of the right liver lobe (RLL) and ADC and SNR were calculated. Results: ADC in RLL tended to be lower at 3 T MRI. Least inter-subject ADC variability was found with RT in the middle RLL at 3 T. Highest ADCs were found caudally in the RLL. Significant differences in ADC between middle and caudal RLL were calculated in FB and RT at 3 T and FB and BH at 1.5 T, respectively. No significant difference in SNR was found between 3 T and 1.5 T. There were significantly more artifacts in the left liver lobe (LLL) compared to the RLL in all sequences and in the LLL at 3 T compared to 1.5 T. Conclusion: Our study suggests that longitudinal hepatic ADC measurements should be performed using equivalent field strength, b-values, and acquisition technique, given influence of these factors on ADC measurements.展开更多
Background: Our aim was to investigate the frequency of elevated liver enzymes and NAFLD in patients with known insulin resistance during 15 years of follow-up. Methods: Subjects with insulin resistance were identifie...Background: Our aim was to investigate the frequency of elevated liver enzymes and NAFLD in patients with known insulin resistance during 15 years of follow-up. Methods: Subjects with insulin resistance were identified from a population-based prospective cohort study in Sweden, Malm? Diet and Cancer Study, conducted in 1991-1996. Inall, 285 non-diabetic subjects with insulin resistance established by HOMA-IR (homeostasis model assessment) were invited to do the liver function testing and if elevated, they should be further assessed by radiological examination of the liver, anthropometric measures and blood testing. Results: 165 subjects (57.9%) agreed to do the liver function testing. Of these, 25 subjects (15%) had elevated liver enzymes. After exclusion of other diseases, 5 of the remaining 21 subjects (23.8%) had radiological signs of steatosis. Liver steatosis significantly correlated with ALT (alanine aminotransferase) (p = 0.04), HOMA-IR (p = 0.00) and the metabolic syndrome (p = 0.03). 80% of the subjects with NAFLD had either developed type 2 diabetes mellitus or had impaired fasting glucose and 80% fulfilled the WHO-criteria for the metabolic syndrome, which were of significant differences to the group without NAFLD. Conclusion: The risk of developing elevated liver enzymes and NAFLD at long-term follow-up in insulin resistant subjects is not insignificant, but mainly associated with the simultaneous development of impaired fasting glucose, established diabetes mellitus and/ or the metabolic syndrome.展开更多
Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in ...Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.展开更多
There are many advantages of combining incretin therapy[glucagon-like peptide-1(GLP-1)receptor agonists and dipeptidyl peptidase-4(DPP-4)inhibitors]with insulin therapy as a glucose-lowering strategy in type2 diabetes...There are many advantages of combining incretin therapy[glucagon-like peptide-1(GLP-1)receptor agonists and dipeptidyl peptidase-4(DPP-4)inhibitors]with insulin therapy as a glucose-lowering strategy in type2 diabetes.One important advantage is the complementary mode of the mechanistic action of incretin and insulin therapy.Another advantage is the reduction in risk of hypoglycemia and weight gain when adding incretin therapy to insulin.Several clinical trials have studied the addition of GLP-1 receptor agonists[exenatide BID(twice daily),lixisenatide,albiglutide]or DPP-4inhibitors(vildagliptin,sitagliptin,saxagliptin,alogliptin,linagliptin)to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist(liraglutide).These studies show improved glycemia in the presence of limited risk for hypoglycemia and weight gain with the combination of incretin therapy with insulin.This article reviews the background and clinical studies on this combination.展开更多
There is overwhelming evidence that hypertension is an important risk factor for both macrovascular and microvascular complications in patients with diabetes,but the problem remains to identify appropriate goals for p...There is overwhelming evidence that hypertension is an important risk factor for both macrovascular and microvascular complications in patients with diabetes,but the problem remains to identify appropriate goals for preventive therapies.A number of guidelines (the European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) 2007,the Joint National Committee (JNC)-Ⅶ 2003,the American Diabetes Association (ADA) 2011) have for example advocated a blood pressure goal of less than 130/80 mmHg,but this suggestion has been challenged by findings in recent trials and meta-analyses (2011).The European Society of Hypertension (ESH) therefore recommends a systolic blood pressure goal of "well below" 140 mmHg.Based on evidence from both randomized controlled trials (hypertension optimal treatment (HOT),action in diabetes and vascular disease:preterax and diamicron MR controlled evaluation (ADVANCE),action to control cardiovascular risk in diabetes (ACCORD)) and observational studies (ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET),international verapamil-trandolapril study (INVEST),treat to new targets (TNT),and the National Diabetes Register (NDR)),it has been shown that the benefit for stroke reduction remains even at lower achieved blood pressure levels,but the risk of coronary events may be uninfluenced or even increased at lower systolic blood pressure levels.In a recent meta-analysis,it was therefore concluded that the new recommended goal should be 130-135 mmHg systolic blood pressure for most patients with type 2 diabetes.Other risk factors should also be controlled with a more ambitious strategy applied in the younger patients with shorter diabetes duration,but a more cautious approach in the elderly and frail patients with a number of vascular or non-vascular co-morbidities.In patients from East Asia,such as China,the stroke risk is relatively higher than the risk of coronary events.This must also be taken into consideration for individualized goal setting in relation to total risk,for example in patients from stroke-prone families.In conclusion,the current strategy is to have a more individualized approach to risk factor control in patients with type 2 diabetes,also relevant for blood pressure control.展开更多
Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with aci...Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.展开更多
Background:Unresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma(PDAC).This study aimed to identify preoperative risk factors for metastatic disease diagnosed at ...Background:Unresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma(PDAC).This study aimed to identify preoperative risk factors for metastatic disease diagnosed at surgical exploration and to investigate and compare survival in resected and nonresected patients.Methods:Patients were identified from the Swedish National Pancreatic and Periampullary Cancer Registry 2010-2018.Predictors of metastatic disease were evaluated with a multivariable logistic regression model,and survival was evaluated with Kaplan-Meier estimates and log-rank tests.Results:In total,1938 patients with PDAC were scheduled for surgery.An unresectable situation was diagnosed intraoperatively in 399 patients(20.6%),including 234(12.1%)with metastasized disease.Independent risk factors for metastasis were involuntary weight loss(OR=1.72;95%CI:1.27-2.33)and elevated carbohydrate antigen 19-9(CA19-9)(35-599 U/m L,OR=1.79,95%CI:1.11-2.89;≥600 U/m L,OR=3.24,95%CI:2.04-5.17).Overall survival was lower among patients with metastasized disease than that among patients with a resectable tumor(P<0.001).Conclusions:Involuntary weight loss and an elevation of CA19-9 are preoperative risk factors for diagnosing metastasized disease during surgical exploration.展开更多
AIM:To examine whether rendezvous endoscopic retrograde cholangiopancreatography(ERCP)is associated with less pancreatic damage,measured as leakage of proenzymes,than conventional ERCP.METHODS:Patients(n=122)with symp...AIM:To examine whether rendezvous endoscopic retrograde cholangiopancreatography(ERCP)is associated with less pancreatic damage,measured as leakage of proenzymes,than conventional ERCP.METHODS:Patients(n=122)with symptomatic gallstone disease,intact papilla and no ongoing inflammation,were prospectively enrolled in this case-controldesigned study.Eighty-one patients were subjected to laparoscopic cholecystectomy and if intraoperative cholangiography suggested common bile duct stones(CBDS),rendezvous ERCP was performed intraoperatively(n=40).Patients with a negative cholangiogram constituted the control group(n=41).Another 41 patients with CBDS,not subjected to surgery,underwent conventional ERCP.Pancreatic proenzymes,procarboxypeptidase B and trypsinogen-2 levels in plasma,were analysed at 0,4,8 and 24 h.The proenzymes were determined in-house with a double-antibody enzyme linked immunosorbent assay.Pancreatic amylase was measured by an enzymatic colourimetric modular analyser with the manufacturer’s reagents.All samples were blinded at analysis.RESULTS:Post ERCP pancreatitis(PEP)occurred in3/41(7%)of the patients cannulated with conventional ERCP and none in the rendezvous group.Increased serum levels indicating pancreatic leakage were significantly higher in the conventional ERCP group compared with the rendezvous ERCP group regarding pancreatic amylase levels in the 4-and 8-h samples(P=0.0015;P=0.03),procarboxypeptidase B in the4-and 8-h samples(P<0.0001;P<0.0001)and trypsinogen-2 in the 24-hour samples(P=0.03).No differences in these markers were observed in patients treated with rendezvous cannulation technique compared with patients that underwent cholecystectomy alone(control group).Post procedural concentrations of pancreatic amylase and procarboxypeptidase B were significantly correlated with pancreatic duct cannulation and opacification.CONCLUSION:Rendezvous ERCP reduces pancreatic enzyme leakage compared with conventional ERCP cannulation technique.Thus,laparo-endoscopic technique can be recommended with the ambition to minimise the risk for post ERCP pancreatitis.展开更多
文摘Portal hypertension(PH)is a major complication of chronic liver disease,often leading to serious clinical consequences such as variceal bleeding,ascites,and splenomegaly.The current gold standard for PH diagnosis,namely,hepatic venous pressure gradient measurement,is invasive and not widely available.Transient elastography has emerged as a non-invasive alternative for assessing liver stiffness(LS),and recent studies have highlighted the potential role of splenic stiffness(SS)in evaluating PH severity.This narrative review summarizes the available evidence on the utility of splenic transient elastography in assessing PH.We evaluated its diagnostic accuracy,technical challenges,and clinical applications,particularly in distinguishing between cirrhotic PH(CPH)and noncirrhotic PH(NCPH).A comprehensive literature search was conducted using the PubMed database,focusing on studies that assess splenic elastography in the diagnosis and prognosis of PH.This review compares splenic elastography with other non-invasive imaging modalities,including MR elastography and shearwave elastography.Additionally,we examined the role of SS using elastography in predicting the presence of esophageal varices and its potential impact on reducing the need for endoscopic screening.Studies have demonstrated that splenic elastography correlates well with PH severity,with cut-off values ranging between 45 kPa and 50 kPa for significant PH detection.Splenic elastography,when combined with platelet count and LS measurements,improves diagnostic accuracy and risk stratification for the occurrence of variceal bleeding.Despite its clinical promise,technical challenges such as patient positioning,body habitus,and probe selection remain key limitations.Notably,splenic elastography may be particularly useful in diagnosing NCPH,where LS remains normal but PH is present.Splenic transient elastography is a valuable adjunct in the non-invasive assessment of PH.Its ability to predict varices,differentiate between CPH and NCPH,and reduce unnecessary endoscopies suggests that it should be incorporated into routine hepatology practice.Future research should focus on refining SS cut-offs,evaluating its cost-effectiveness,and integrating splenic elastography into clinical guidelines for PH management.
基金supported by grants from the Top Medical Expert Team of Wuxi Taihu Talent Plan(Grant Nos.DJTD202106,GDTD202105 and YXTD202101)Medical Key Discipline Program of Wuxi Health Commission(Grant Nos.ZDXK2021007 and CXTD2021005)+1 种基金Top Talent Support Program for Young and MiddleAged People of Wuxi Health Committee(Grant No.BJ2023090)Scientific Research Program of Wuxi Health Commission(Grant Nos.Z20210 and M202208).
文摘With the prevalence of obesity,metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide and can cause a series of serious complications.The pathogenesis of MASLD is complex,characterized by oxidative stress,impaired mitochondrial function and lipid metabolism,and cellular inflammation.Mitochondrial biology and function are central to the physiology of the liver.It has been suggested that mitochondrial oxidative stress plays a crucial role in MASLD progression.Excessive oxidative stress response is an important trigger for the occurrence and development of MASLD.In this review,we aim to focus on the recent advances in understanding mitochondrial oxidative stress-related mechanisms in the progression of MASLD.The in-depth elaboration of its related mechanisms is hoped to help find effective methods for treating MASLD.
文摘Postural tachycardia syndrome(POTS)is a chronic autonomic disorder characterized by excessive heart rate elevation upon standing or head-up tilt,in the absence of orthostatic hypotension.This debilitating condition affects primarily young to middle-aged individuals,particularly women,and substantially influences quality of life.The main present-ing symptoms are lightheadedness,palpitations,exercise intolerance,and cognitive impairment.POTS is of particular importance to cardiologists,given its prominent cardiovascular symptoms.The diagnostic criteria for POTS include a sustained heart rate increase of more than 30 beats per minute upon standing or head-up tilt;symptoms of orthostatic intolerance lasting at least 3 months;and exclusion of other causes.The exact etiology of POTS is unknown,but mul-tiple possible etiologies leading to a similar clinical phenotype have been proposed.Early intervention and appropri-ate management can improve symptoms.Treatment strategies include lifestyle modifications,pharmacotherapy,and tailored conditioning programs.Non-pharmacologic options are the first line treatment.Prognosis varies widely:POTS can be a temporary condition for some individuals but a chronic and debilitating condition for others.Further research is necessary to elucidate the pathophysiology and optimize treatment strategies for this condition.
基金Bengt Ihre Foundation,No.SLS-594-301 and SLS-789091
文摘Serum levels of cartilage oligomeric matrix protein(COMP) has been presented as a biomarker of liver fibrosis in several cross-sectional studies. COMP is also an essential mediator in carcinoma development and has also been associated with hepatocellular carcinoma. We present a prospective analysis of this biomarker in38 patients with chronic hepatitis C who were subject to eradication therapy with direct acting antivirals. We confirm previous studies associating COMP elevation with liver cirrhosis. We also show how viral levels are correlated with COMP at baseline. In our prospective analysis, we report that successful eradication of hepatitis C results in improvement in liver stiffness and laboratory liver function tests at 1 year follow-up. In contrast, median COMP-levels remain unchanged during the study period. We conclude that the biomarker potential of COMP in the prospective evaluation of liver diseases, remains to be elucidated.
文摘Objective: Hyponatremia is the most common electrolyte imbalance. The initial treatment decision is based on clinical evaluation of patient volume status but an accurate assessment is difficult, particularly differentiating mild hypovolemia from euvolemia. The aim of this study is to examine if biomarkers are valuable in the early determination of volume status and SIADH diagnosis. Methods: Blood samples were collected from an unselected patient population at entry to the Emergency Department. If the plasma sodium level (P-Na) was ≤125 mmol/L, the sample was frozen for further analysis. Mid-regional pro-atrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), C-terminal prepro-vasopressin (copeptin), pro-endothelin-1 (proET-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were analysed. A comprehensive assessment of volume status and underlying causes was made after discharge blinded for biomarker results. Results: A total of 81 patients were included. A well substa ntiated volemic state (hypo/eu/hypervolemia) was established in 72 patients (mean age 76 years, 65% women, median P-Na 119 mmol/L). A significant association was observed between MR-proANP levels and volemic state (p = 0.0001). Data was specifically analysed with respect to distinguishing hypo- from euvolemia (n = 59) using logistic regression. In a crude analysis, MR-proANP was significantly related to euvolemia (OR: 2.54 per SD of MR-proANP, 95% CI 1.32 - 4.86, p = 0.005) and remained so after the multivariate backward elimination model (OR: 2.45 per SD of MRproANP, 95% CI 1.22 - 4.91, p = 0.012.), whereas the other studied biomarkers were not. Copeptin levels were not associated with a diagnosis of SIADH. Conclusions: MR-proANP may be of value in early determination of volume status in hyponatremic patients.
基金This study was supported by the Pediatric Heart Center at Skåne University Hospital Lund and Lund University,and by the Swedish Children’s Heart Association.
文摘Background:Parents of children with complex right ventricular outflow tract(RVOT)anomalies are confronted with their child’s need for heart surgery early in life and repeated reoperations later on.Preoperative assessment needs to be performed whenever an indication for reoperation is suspected.The aim was to illuminate the experiences of parents of children diagnosed with RVOT anomalies,in particular,how they experience their child’s heart disease and everyday life during the assessment and after the decision on whether to perform a reoperation.Method:Individual interviews(n=27)were conducted with nine parents on three occasions between 2014 and 2016 and analyzed using reflexive thematic analysis.Results:The analysis resulted in the following five main coexisting themes:The heart surgery keeps my child alive illuminates parents’experiences during and after the assessment and emphasizes that heart surgery,although dreaded,is central for their child’s survival;Everyday struggles illuminates the different struggles parents had to face to ensure that their child would be in the best possible condition;the remaining three themes,Unconditional love,Trust in life,and Togetherness,illuminate the ways in which the parents gained inner strength and confidence in their everyday lives.Conclusion:Although the parents were grateful for the assessment and had learned to navigate among the fears it aroused,they experienced several distressing situations during the assessment process that should be addressed.By inviting both the parents and their child to participate in the child’s care,individualized support can take into account the needs of both parents and child.
基金Supported by the Development Foundation of Region Skane,No.REGSKANE-818781 and No.2018-Projekt0024the Foundation Skane University Hospital,No.2020-0000028.
文摘BACKGROUND The enteric nervous system(ENS)is situated along the entire gastrointestinal tract and is divided into myenteric and submucosal plexuses in the small and large intestines.The ENS consists of neurons,glial cells,and nerves assembled into ganglia,surrounded by telocytes,interstitial cells of Cajal,and connective tissue.Owing to the complex spatial organization of several interconnections with nerve fascicles,the ENS is difficult to examine in conventional histological sections of 3-5μm.AIM To examine human ileum full-thickness biopsies using X-ray phase-contrast nanotomography without prior staining to visualize the ENS.METHODS Six patients were diagnosed with gastrointestinal dysmotility and neuropathy based on routine clinical and histopathological examinations.As controls,fullthickness biopsies were collected from healthy resection ileal regions after hemicolectomy for right colon malignancy.From the paraffin blocks,4-μm thick sections were prepared and stained with hematoxylin and eosin for localization of the myenteric ganglia under a light microscope.A 1-mm punch biopsy(up to 1 cm in length)centered on the myenteric plexus was taken and placed into a Kapton®tube for mounting in the subsequent investigation.X-ray phase-contrast tomography was performed using two custom-designed laboratory setups with micrometer resolution for overview scanning.Subsequently,selected regions of interest were scanned at a synchrotron-based end-station,and high-resolution slices were reported.In total,more than 6000 virtual slices were analyzed from nine samples.RESULTS In the overview scans,the general architecture and quality of the samples were studied,and the myenteric plexus was localized.High-resolution scans revealed details,including the ganglia,interganglional nerve fascicles,and surrounding tissue.The ganglia were irregular in shape and contained neurons and glial cells.Spindle-shaped cells with very thin cellular projections could be observed on the surface of the ganglia,which appeared to build a network.In the patients,there were no alterations in the general architecture of the myenteric ganglia.Nevertheless,several pathological changes were observed,including vacuolar degeneration,autophagic activity,the appearance of sequestosomes,chromatolysis,and apoptosis.Furthermore,possible expulsion of pyknotic neurons and defects in the covering cellular network could be observed in serial slices.These changes partly corresponded to previous light microscopy findings.CONCLUSION The analysis of serial virtual slices could provide new information that cannot be obtained by classical light microscopy.The advantages,disadvantages,and future possibilities of this method are also discussed.
文摘Hyponatremia is a severe electrolyte disturbance associated with substantial morbidity and mortality. It often poses a diagnostic and therapeutic challenge. Accurate assessment of patient fluid-volume status is central to effective management. This pilot study aimed to evaluate the usefulness of the Cheetah NICOM bioreactance system and apelin in early differentiation between hypo- and euvolemia in patients with severe hyponatremia. <strong>Methods:</strong> Patients > 50 years of age with a serum sodium ≤ 125 mmol/L were eligible for inclusion after written informed consent. Blood- and urine analyses of cardiovascular load (NT-proBNP), osmotic stress (copeptin, apelin, osmolality, sodium), mineralocorticoid status (aldosterone, renin) and sympathetic activity (methoxycathecholamines) were analysed at baseline and after isotonic sodium chloride infusion. Bedside bioreactance examination was used to visualise parameters, including stroke volume before and after passive leg raise test. Classification of volume status was made retrospectively blinded for biomarker and bioreactance results. <strong>Results:</strong> 8 patients (4 hypovolemic and 4 euvolemic), 79 years old, median plasma sodium 120 mmol/L were included. At the Emergency Department volume status was misclassified in all hypo- and in 2 of 4 euvolemic patients. Apelin was significantly higher in hypovolemic patients ((299 vs. 175 ng/ml), p = 0.021). All hypovolemic, but none of the euvolemic, patients had a level above 250 ng/ml. Copeptin did not differ between groups. All patients in the hypovolemic group increased their stroke volume after passive leg raise. <strong>Conclusions:</strong> Apelin seems to be a promising future biomarker in the early management of severe hyponatremia. Bioreactance measurements may offer a supplement to bedside evaluation of volume status.
文摘Background: Several studies have shown that persons with schizophrenia (PWS) suffer from severely reduced quality of life (QoL). Impaired social functioning is a defining characteristic of schizophrenia (SZ) and social cognition deficits affect interpersonal relations and outcomes such as independent living, vocational functioning and employment status. Some studies have demonstrated important socio-cultural aspects of SZ, for instance by examining experiences of SZ in different developing countries and among minority groups in the Western world. The socio-cultural context is central to understanding patients’ experiences in any society, however. Using an anthropological approach, we use qualitative research methods to examine patient perspectives on SZ. Sampling and Methods: In-depth qualitative interviews are carried out with SZ patients in France, the UK and the USA representing diversity in Western mental health systems. Results: To the participants, the most important QoL aspects are close relations and support from loved ones, a safe home and comfort zone, and meaningful daily activities. Normalisation and independence act as central themes to patients’ QoL and hopes for social integration. The participants need a buffer zone consisting of social relations, a home and daily occupation that is flexible and may balance issues of equality/inequality, abnormality/normality, and dependence/independence. Conclusion: By using participatory methods, PWS may be involved in shaping their own treatment and recovery plans based on what is subjectively meaningful and beneficial to their mental health. QoL and functioning are closely linked to the socio-cultural context in which health care structures go hand in hand with health care cultures that shape patients’ expectations and preferences.
文摘Problem gambling is over-represented in patients treated for substance use disorders, but substance-specific prevalence of problem gambling is rarely reported. In specialized addiction treatment facilities for opioid maintenance treatment and for alcohol and prescription drug dependence, respectively, 129 patients were screened for problem gambling using the NODS-CLiP. The lifetime prevalence of problem gambling was markedly higher in opioid maintenance treatment (61 percent) than in alcohol and prescription drug dependence treatment (11 percent, p < 0.001). When controlling for gender and age, problem gambling remained significantly associated with opioid maintenance treatment. The present study demonstrated a very high prevalence of lifetime problem gambling in opioid maintenance treatment patients. This calls for active screening for problem gambling in substance use disorder patients, and mainly in treatment for opioid dependence.
文摘Background: Several studies analyze how surgical delay affects patients with hip fracture. The aim of this study was to identify the causes of surgical delay and demographic characteristics in patients with hip fracture who had delays longer than 24 hours from admission to hospital. Methods: Quantitative retrospective register study of 484 patients was consecutively included during the period November 1, 2010 and October 31, 2011 in the University Hospital in Lund (Sweden). Results: A frequency of 29.4% had a surgical delay longer than 24 hours. The main reasons for delays to surgery were lack of theatre facilities (54%), medical unstable patient (16%) and anticoagulant treatment (10%). Of all patients, 69% (n = 332) were women and 31% (n = 151) were men. The mean age for women were 83.6 (CI 83-85) vs. 79 (CI 77-81) for men, respectively. The most common type of hip fracture was displaced cervical hip fracture (39%, n = 188) with a majority of fractures in male patients. In total, women suffered hip fractures to a greater extent than men (69% vs. 31%, p = 0.016), but no relationship was found with respect to the fracture type and age (p = 0.358). Conclusion: The main result demonstrated that delays longer than 24 hours were due to lack of theatre facilities. Further researches have to be done in order to investigate whether lack of theatre facilities depends on improper operation planning and/or on lack of medical staff.
文摘Purpose: To evaluate the impact of field strength and respiratory motion control on diffusion-weighted MR imaging (DWI) of the liver at 1.5 and 3 T. Material and Methods: Three DWI sequences using seven b-values from 20 - 400 s/mm2 were designed with identical parameters but with different handling of respiratory motion [respiratory triggered (RT), free breathing (FB), breath hold (BH)] on 3 T and 1.5 T. Thirteen volunteers were examined at a 3 T and six of them also at a 1.5 T magnet. DW images were analyzed quantitatively and qualitatively. Regions of interest were placed in cranial, middle and caudal parts of the right liver lobe (RLL) and ADC and SNR were calculated. Results: ADC in RLL tended to be lower at 3 T MRI. Least inter-subject ADC variability was found with RT in the middle RLL at 3 T. Highest ADCs were found caudally in the RLL. Significant differences in ADC between middle and caudal RLL were calculated in FB and RT at 3 T and FB and BH at 1.5 T, respectively. No significant difference in SNR was found between 3 T and 1.5 T. There were significantly more artifacts in the left liver lobe (LLL) compared to the RLL in all sequences and in the LLL at 3 T compared to 1.5 T. Conclusion: Our study suggests that longitudinal hepatic ADC measurements should be performed using equivalent field strength, b-values, and acquisition technique, given influence of these factors on ADC measurements.
文摘Background: Our aim was to investigate the frequency of elevated liver enzymes and NAFLD in patients with known insulin resistance during 15 years of follow-up. Methods: Subjects with insulin resistance were identified from a population-based prospective cohort study in Sweden, Malm? Diet and Cancer Study, conducted in 1991-1996. Inall, 285 non-diabetic subjects with insulin resistance established by HOMA-IR (homeostasis model assessment) were invited to do the liver function testing and if elevated, they should be further assessed by radiological examination of the liver, anthropometric measures and blood testing. Results: 165 subjects (57.9%) agreed to do the liver function testing. Of these, 25 subjects (15%) had elevated liver enzymes. After exclusion of other diseases, 5 of the remaining 21 subjects (23.8%) had radiological signs of steatosis. Liver steatosis significantly correlated with ALT (alanine aminotransferase) (p = 0.04), HOMA-IR (p = 0.00) and the metabolic syndrome (p = 0.03). 80% of the subjects with NAFLD had either developed type 2 diabetes mellitus or had impaired fasting glucose and 80% fulfilled the WHO-criteria for the metabolic syndrome, which were of significant differences to the group without NAFLD. Conclusion: The risk of developing elevated liver enzymes and NAFLD at long-term follow-up in insulin resistant subjects is not insignificant, but mainly associated with the simultaneous development of impaired fasting glucose, established diabetes mellitus and/ or the metabolic syndrome.
基金supported in part by the Outsmarting Osteosarcoma Hero Award(Because of Sydney)the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award+23 种基金supported by NCI R01CA201035,R01CA240711,R01CA229893DoD W81XWH-18-1-0223UCLA SPORE in Prostate Cancer(P50 CA092131)JCCC Cancer support grant from NIH P30 CA016042(PI:Teitell)Knut and Alice Wallenberg FoundationBertha Kamprad FoundationDavid H.Koch Prostate Cancer Foundation Young Investigator AwardSwedish Research CouncilSwedish Cancer SocietySIPEA FoundationSwedish Childhood Cancer FoundationJohn and Augusta Perssons FoundationRoyal Physiographic Society of LundFranke and Margareta Bergqvist FoundationCrafoord FoundationLund University Medical Faculty research time allocation award,IngaBrittArne Lundberg Research Foundation,the German Research Foundation(552440240)the German Cancer Consortium(DKTK)the German Federal Ministry of Education and Research(BMBFgrant no.01KD2206A/SATURN3)funding support from the Children’s Discovery Institute of the St.Louis Children’s Hospital.Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory(RRID:SCR_022789)the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center(JCCC)Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697。
文摘Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.
文摘There are many advantages of combining incretin therapy[glucagon-like peptide-1(GLP-1)receptor agonists and dipeptidyl peptidase-4(DPP-4)inhibitors]with insulin therapy as a glucose-lowering strategy in type2 diabetes.One important advantage is the complementary mode of the mechanistic action of incretin and insulin therapy.Another advantage is the reduction in risk of hypoglycemia and weight gain when adding incretin therapy to insulin.Several clinical trials have studied the addition of GLP-1 receptor agonists[exenatide BID(twice daily),lixisenatide,albiglutide]or DPP-4inhibitors(vildagliptin,sitagliptin,saxagliptin,alogliptin,linagliptin)to ongoing insulin therapy or adding insulin to ongoing therapy with a GLP-1 receptor agonist(liraglutide).These studies show improved glycemia in the presence of limited risk for hypoglycemia and weight gain with the combination of incretin therapy with insulin.This article reviews the background and clinical studies on this combination.
基金Project (No. VR2009-1032) supported by a Strategic Research Grant for Excellence in Epidemiological Research from the Research Council,Sweden,to the Lund University for which the author is the coordinator (www.med.lu.se/epihealth)
文摘There is overwhelming evidence that hypertension is an important risk factor for both macrovascular and microvascular complications in patients with diabetes,but the problem remains to identify appropriate goals for preventive therapies.A number of guidelines (the European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) 2007,the Joint National Committee (JNC)-Ⅶ 2003,the American Diabetes Association (ADA) 2011) have for example advocated a blood pressure goal of less than 130/80 mmHg,but this suggestion has been challenged by findings in recent trials and meta-analyses (2011).The European Society of Hypertension (ESH) therefore recommends a systolic blood pressure goal of "well below" 140 mmHg.Based on evidence from both randomized controlled trials (hypertension optimal treatment (HOT),action in diabetes and vascular disease:preterax and diamicron MR controlled evaluation (ADVANCE),action to control cardiovascular risk in diabetes (ACCORD)) and observational studies (ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET),international verapamil-trandolapril study (INVEST),treat to new targets (TNT),and the National Diabetes Register (NDR)),it has been shown that the benefit for stroke reduction remains even at lower achieved blood pressure levels,but the risk of coronary events may be uninfluenced or even increased at lower systolic blood pressure levels.In a recent meta-analysis,it was therefore concluded that the new recommended goal should be 130-135 mmHg systolic blood pressure for most patients with type 2 diabetes.Other risk factors should also be controlled with a more ambitious strategy applied in the younger patients with shorter diabetes duration,but a more cautious approach in the elderly and frail patients with a number of vascular or non-vascular co-morbidities.In patients from East Asia,such as China,the stroke risk is relatively higher than the risk of coronary events.This must also be taken into consideration for individualized goal setting in relation to total risk,for example in patients from stroke-prone families.In conclusion,the current strategy is to have a more individualized approach to risk factor control in patients with type 2 diabetes,also relevant for blood pressure control.
基金supported from grants of Swedish Research CouncilSwedish Cancerfonden+2 种基金Albert P?hlsson FoundationCrafoord Foundationfoundation of Region Skane University Hospital, Lund, Sweden
文摘Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.
基金supported by a Government Grant for Clinical Research(http://www.skane.se/fou/alf)The Bengt Ihre foundationThe Swedish Cancer Foundation。
文摘Background:Unresectable disease is sometimes diagnosed during surgery in patients with pancreatic ductal adenocarcinoma(PDAC).This study aimed to identify preoperative risk factors for metastatic disease diagnosed at surgical exploration and to investigate and compare survival in resected and nonresected patients.Methods:Patients were identified from the Swedish National Pancreatic and Periampullary Cancer Registry 2010-2018.Predictors of metastatic disease were evaluated with a multivariable logistic regression model,and survival was evaluated with Kaplan-Meier estimates and log-rank tests.Results:In total,1938 patients with PDAC were scheduled for surgery.An unresectable situation was diagnosed intraoperatively in 399 patients(20.6%),including 234(12.1%)with metastasized disease.Independent risk factors for metastasis were involuntary weight loss(OR=1.72;95%CI:1.27-2.33)and elevated carbohydrate antigen 19-9(CA19-9)(35-599 U/m L,OR=1.79,95%CI:1.11-2.89;≥600 U/m L,OR=3.24,95%CI:2.04-5.17).Overall survival was lower among patients with metastasized disease than that among patients with a resectable tumor(P<0.001).Conclusions:Involuntary weight loss and an elevation of CA19-9 are preoperative risk factors for diagnosing metastasized disease during surgical exploration.
基金Supported by KI-fonder at Karolinska Institutet,Bengt Ihre Foundation,Stockholm,Swedenthe Foundations of Researchat the University Hospital,Hedbergs Stiftelse and Mossbergs Stiftelse,Malm Sweden,Research Grants from the Stockholm County and Skane County Council(ALF)
文摘AIM:To examine whether rendezvous endoscopic retrograde cholangiopancreatography(ERCP)is associated with less pancreatic damage,measured as leakage of proenzymes,than conventional ERCP.METHODS:Patients(n=122)with symptomatic gallstone disease,intact papilla and no ongoing inflammation,were prospectively enrolled in this case-controldesigned study.Eighty-one patients were subjected to laparoscopic cholecystectomy and if intraoperative cholangiography suggested common bile duct stones(CBDS),rendezvous ERCP was performed intraoperatively(n=40).Patients with a negative cholangiogram constituted the control group(n=41).Another 41 patients with CBDS,not subjected to surgery,underwent conventional ERCP.Pancreatic proenzymes,procarboxypeptidase B and trypsinogen-2 levels in plasma,were analysed at 0,4,8 and 24 h.The proenzymes were determined in-house with a double-antibody enzyme linked immunosorbent assay.Pancreatic amylase was measured by an enzymatic colourimetric modular analyser with the manufacturer’s reagents.All samples were blinded at analysis.RESULTS:Post ERCP pancreatitis(PEP)occurred in3/41(7%)of the patients cannulated with conventional ERCP and none in the rendezvous group.Increased serum levels indicating pancreatic leakage were significantly higher in the conventional ERCP group compared with the rendezvous ERCP group regarding pancreatic amylase levels in the 4-and 8-h samples(P=0.0015;P=0.03),procarboxypeptidase B in the4-and 8-h samples(P<0.0001;P<0.0001)and trypsinogen-2 in the 24-hour samples(P=0.03).No differences in these markers were observed in patients treated with rendezvous cannulation technique compared with patients that underwent cholecystectomy alone(control group).Post procedural concentrations of pancreatic amylase and procarboxypeptidase B were significantly correlated with pancreatic duct cannulation and opacification.CONCLUSION:Rendezvous ERCP reduces pancreatic enzyme leakage compared with conventional ERCP cannulation technique.Thus,laparo-endoscopic technique can be recommended with the ambition to minimise the risk for post ERCP pancreatitis.
