The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream...The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.展开更多
Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 ...Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogram-ming, reversing the epigenetic configuration of differ-entiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mecha-nisms underlying these roles.展开更多
Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, ...Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo 1H MRS is a fast, safe, non-invasive method forthe quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.展开更多
Primary liver cancer is amongst the commonest tumors worldwide,particularly in parts of the developing world,and is increasing in incidence. Over the past three decades,surgical hepatic resection has evolved from a hi...Primary liver cancer is amongst the commonest tumors worldwide,particularly in parts of the developing world,and is increasing in incidence. Over the past three decades,surgical hepatic resection has evolved from a high risk,resource intensive procedure with limited application,to a safe and commonly performed operation with a range of indications. This article reviews the approach to surgical resection for malignancies such as hepatocellular cancer,metastatic liver de-posits and neuroendocrine tumors. Survival data after resection is also reviewed,as well as indications for curative resection.展开更多
Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the dia...Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.展开更多
Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and...Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiologi- cal processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response.展开更多
Ultrasound (US) is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of ...Ultrasound (US) is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of specific contrast media and the development of specialized imaging techniques. Ultrasound now can fully characterise the enhancement pattern of hepatic lesions, similar to that achieved with contrast enhanced multiphasic computed tomography (CT) and magnetic resonance imaging (MRI). US contrast agents are safe, well-tolerated and have very few contraindications. Furthermore, real-time evaluation of the vascularity of focal liver lesions has become possible with the use of the newer microbubble contrast agents. This article reviews the enhancement pattern of the most frequent liver lesions seen, using the second generation US contrast media. The common pitfalls for each type of lesion are discussed. The recent developments in US contrast media and specific imaging techniques have been a major advance and this technique, in view of the intrinsic advantages of US, will undoubtedly gain popularity in the years to come.展开更多
Haemangiomas are the most common solitary benign neoplasm of the liver with an incidence ranging from 5% to 20%. Although usually small and asymptomatic, they may reach considerable proportions and rarely give rise to...Haemangiomas are the most common solitary benign neoplasm of the liver with an incidence ranging from 5% to 20%. Although usually small and asymptomatic, they may reach considerable proportions and rarely give rise to life-threatening complications. Surgical intervention is required for incapacitating symptoms, established complications, and diagnostic uncertainty. The resection of haemangiomas demands meticulous surgical technique, owing to their high vascularity and the concomitant risk of intra-operative haemorrhage. Laparoscopic resection of giant haemangiomas is even more challenging, and has only been reported twice. We here report the case of a giant 10 cm liver haemangioma which was successfully resected laparoscopically using the laparoscopic HabibTM 4×, a bipolar radiofrequency device, without clamping major vessels and with minimal blood loss. Transfusion of blood or blood products was not required. The patient had an uneventful recovery and was asymptomatic at 7-mo follow-up.展开更多
AIM: To study costs of laparoscopic and open liver and pancreatic resections, all the compiled data from available observational studies were systematically reviewed.
Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This arti...Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This article examines the various assessment methods currently available from gold standard liver biopsy to serological markers and imaging. Ultrasound is one of the most widely used imaging modalities in clinical practice and is already a first-line diagnostic tool for liver disease. Microbubble ultrasound contrast agents allow higher resolution images to be obtained and functional assessments of microvascular change to be carried out. The role of these agents in quantifying the state of hepatic injury is discussed as a viable method of determining the stage and grade of liver disease in patients with hepatitis C. Although currently confined to specialist centres, the availability of microbubble contrast-enhanced ultrasound will inevitably increase in the clinical setting.展开更多
Mitochondrial dysfunction and endoplasmic reticulum stress(ERS)are global processes that are interrelated and regulated by several stress factors.Nitric oxide(NO)is a multifunctional biomolecule with many varieties of...Mitochondrial dysfunction and endoplasmic reticulum stress(ERS)are global processes that are interrelated and regulated by several stress factors.Nitric oxide(NO)is a multifunctional biomolecule with many varieties of physiological and pathological functions,such as the regulation of cytochrome c inhibition and activation of the immune response,ERS and DNA damage;these actions are dose-dependent.It has been reported that in embryonic stem cells,NO has a dual role,controlling differentiation,survival and pluripotency,but the molecular mechanisms by which it modulates these functions are not yet known.Low levels of NO maintain pluripotency and induce mitochondrial biogenesis.It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca^(2+)flux that induce ERS.Thus,at high concentrations,NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines.Nevertheless,many studies have demonstratedthe need for physiological levels of NO for a proper ERS response.In this review,we stress the importance of the relationships between NO levels,ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.展开更多
Objectives: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. Design...Objectives: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. Design: We retrospectively reviewed brain magnetic resonance imaging in patients with congenital muscular dystrophy and FKRP gene mutations. Patients: Thirteen patients with congenital muscular dystrophy and mutations in the FKRP gene. Results: Five of the 13 patients had the typical phenotype originally described for congenital muscular dystrophy (MDC1C) with normal intelligence and normal brain magnetic resonance imaging while 3 other patients had isolated cerebellar cysts and mental retardation without any other sign of posterior fossa of supratentorial abnormalities. In the remaining 5 patients cerebellar cysts were associated with structural brain changes involving the posterior fossa and the cortex, ranging from focal unilateral periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. In 2 of these 5 patients the severity and distribution of changes resembled muscle-eye-brain disease in 1 patient who had mild Walker-Warburg syndr ome. The distribution of FKRP gene mutations identified in this group of patients did not reveal any obvious association with the severity of central nervous system involvement. Conclusions: The severity of central nervous system involvement observed in our patients in contrast broadly reflected the severity of the disruption of α-dystroglycan glycosylation. In particular, dystroglycan expression was almost absent in the patients with muscle-eye-brain diseaselike phenotype and less severely reduced in the patients with congenital muscular dystrophy (MDC1C) with or without cerebellar cysts. This study further highlights the central role that dystroglycan has in neuronal migration.展开更多
Dear Editor,Varicocele is a common cause of male infertility,but in the course of a diagnostic infertility workup,other underlying problems are often found.Up to two-thirds of patients with nonidiopathic male infertil...Dear Editor,Varicocele is a common cause of male infertility,but in the course of a diagnostic infertility workup,other underlying problems are often found.Up to two-thirds of patients with nonidiopathic male infertility have at least two possible etiologies.展开更多
Background: Kisspeptin has been demonstrated to affect the attainment of puberty in multiple species, presumably through its actions on GnRH and LH. It has previously been found there is an increase in expression of h...Background: Kisspeptin has been demonstrated to affect the attainment of puberty in multiple species, presumably through its actions on GnRH and LH. It has previously been found there is an increase in expression of hypothalamic in the rat and the monkey coincident with puberty. Whether a similar phenomenon occurs in the pig remains to be determined. The objectives of the current experiments were to determine 1) Plasma concentrations of estradiol-17β;2) Anterior pituitary gland concentrations of LH, IGF-I, kisspeptin, and anterior pituitary gland expression of LH-β and GnRH receptor;3) Mediobasal hypothalamus expression of Kiss1 and concentrations of kisspeptin during the peripubertal period in the gilt. Methods: Two experiments were performed, each with 25 crossbred gilts (151 d, 105 kg). Gilts were relocated and exposed to a mature boar beginning on d 1 and continuing throughout the experiments to naturally induce puberty. Gilts that stood immobile within 24 hours of slaughter were considered to have attained puberty. Plasma samples were collected on d 1, 3, and 7 of the first experiment and d 2, 4, 6, and 8 of the second experiment. Gilts were slaughtered on d 7 (experiment 1) or d 8 (experiment 2), when mediobasal hypothalamus (MBH), anterior pituitary glands (AP), and blood were collected. Relative expression of MBH Kiss1 and β-actin and AP GnRH receptor, LH-β, was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Hypothalamic and AP content of kisspeptin were determined by RIA and differences were determined using the GLIMMIX procedure of SAS. Results: Relative expression of Kiss1 was increased (P = 0.005) 2.2 fold in the gilts that had attained puberty in the first experiment, however, those that had attained puberty in the second were not different (P > 0.05) from gilts that had not. Relative expression of GnRH receptor was not different (P > 0.05) between treatments in both experiments. Relative expression of LH-β tended to be decreased (P = 0.09) 0.80 fold in gilts that attained puberty in the first experiment but was not different (P > 0.05) in gilts that attained puberty in the second experiment. AP concentrations of LH were not different (P > 0.05) between treatments in the first experiment and were decreased (P = 0.01) in gilts that attained puberty in the second experiment. AP concentrations of kisspeptin were not different (P > 0.05) in the first experiment but were increased (P = 0.04) in gilts that had attained puberty in the second experiment. MBH concentrations of kisspeptin were increased (P = 0.03) in gilts that had attained puberty in the first experiment but were not different (P > 0.05) between treatments in the second experiment. Conclusions: These data further support the role that MBH expression of Kiss1 and concentrations of kisspeptin and AP concentrations of kisspeptin fluctuate during the peripubertal period and may play a role in the attainment of puberty in the gilt.展开更多
<span style="font-family:Verdana;">Kisspeptin has been demonstrated to affect reproductive cyclicity and the attainment of puberty in multiple species, presumably through its actions on gonadotropin re...<span style="font-family:Verdana;">Kisspeptin has been demonstrated to affect reproductive cyclicity and the attainment of puberty in multiple species, presumably through its actions on gonadotropin releasing hormone and luteinizing hormone. Kisspeptin administration causes increased plasma concentrations of LH in pigs, sheep, and rats. The objective of this experiment was to evaluate changes in the hypothalamic kisspeptin system throughout the estrous cycle in gilts. Estrus was synchronized in forty crossbred gilts (191 d, 121 kg) and estrus detection was performed by exposing gilts to a mature boar. The first day gilts stood immobile was denoted d 1 of the estrous cycle. Blood samples were collected via jugular venipuncture on d 1, 4, 7, 9, 14, 16, and 19 of the estrous cycle. Ten animals were slaughtered on d 1, 9, 14, and 21 of the estrous cycle when medial basal hypothalami, anterior pituitary glands, and blood were collected. Relative expression of hypothalamic kisspeptin (KISS1), kisspeptin receptor (KISS1R), estrogen receptors-a, anterior pituitary gland GnRH receptor, </span><i><span style="font-family:Verdana;">β</span></i><span style="font-family:Verdana;">-actin</span><span style="font-family:Verdana;" "="">,</span><span style="font-family:;" "=""><span style="font-family:Verdana;"> and GAPDH was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Relative expression of KISS1 was increased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.006) 3.2 fold on d 1 versus d 21 and 2.3 fold (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.003) on d 9 versus d 21 of the estrous cycle, but was not different (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 0.05) among the remaining days of the estrous cycle. Relative expression of estrogen receptor-b was decreased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.05) 0.8 fold on d 9 versus d 21 and (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.005) 0.7 fold on d 14 versus d 21, but was not different (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 0.05) among the remaining days. Relative expression of anterior pituitary gland GnRH receptor was increased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> < 0.01) on d 1 and 21 versus d 9 and 14. These data support the notion that medial basal hypothalamic expression of KISS1 changes throughout the estrous cycle and may influence reproductive cyclicity in the gilt.</span></span>展开更多
Objective:Bariatric surgery has been shown to be an effective method of treatment for obstructive sleep apnea(OSA)with long-term benefits,however,the mechanisms of action and the optimum operative procedure remains un...Objective:Bariatric surgery has been shown to be an effective method of treatment for obstructive sleep apnea(OSA)with long-term benefits,however,the mechanisms of action and the optimum operative procedure remains unclear.The aim of this systemic review was to compare the efficacy of laparoscopic sleeve gastrectomy(LSG)and Roux-en-Y gastric bypass(RYGB)in resolving OSA.Methods:A comprehensive search of MEDLINE,Pubmed,Embase,and OVID was performed.Studies that reported OSA resolution in obese patients with BMI>30 kg/m2 were included in the study.RCTs,comparative prospective and matched cohort studies comparing RYGB with LSG were considered for this study.Results:Five studies(309 participants)were included:4 cohort studies and 1 RCT;all with low risk of bias.At 12 months follow-up,there was a trend towards improved resolution of OSA with LSG(OR 0.47,95%CI[0.20 to 1.06];p=0.07)when compared to RYGB.In contrast,there was a trend to poorer weight loss in the LSG group(SMD 3.83,95%CI[-1.82 to 9.48];p=0.18).Similarly,at 36 months follow-up,there was a trend towards better resolution of OSA with LSG(OR 0.52,95%CI[0.16 to 1.71];p=0.28)and a significantly poorer weight loss in LSG when compared to RYGB(SMD 8.25,95%CI[2.91 to 13.58];p=0.002).Conclusion:Despite poorer weight loss following LSG,there is a trend towards increased resolution of sleep apnea post-LSG.These findings suggest the possibility of weight loss independent factors causing OSA resolution,which should be further investigated.Registration:PROSPERO:CRD42018090367.展开更多
Giardia is an enteric protozoan that infects a wide range of vertebrate hosts, being considered a major causative agent of gastrointestinal disease in humans in both developing and developed countries. Giardia infecti...Giardia is an enteric protozoan that infects a wide range of vertebrate hosts, being considered a major causative agent of gastrointestinal disease in humans in both developing and developed countries. Giardia infection has also a significant impact on livestock health, causing diarrhoea and resulting in significant economic lost. Transmission is either direct, through the faecal-oral route, or indirect, through ingestion of contaminated water or food. In this article, we review current knowledge about the epidemiology of giardiasis in different populations in Spain, including humans, livestock, companion animals, and wildlife. Environmental contamination of surface waters and raw foods by Giardia cysts is also addressed. Special relevance has been given to the data available on the molecular characterization of the Giardia isolates obtained from clinical and environmental samples, as determining thespecies/assemblages and subassemblages involved is essential for accurately identifying the parasite and assessing zoonotic transmission. The public health significance of these findings has also been thoroughly discussed.展开更多
Objectives To develop a simple, accurate and reproducible method, which combines macro and histopathological techniques for determining the degree of lipid deposition in genetically modified mice. Method The entire a...Objectives To develop a simple, accurate and reproducible method, which combines macro and histopathological techniques for determining the degree of lipid deposition in genetically modified mice. Method The entire aortas from C57BL/6, ldlr-/- and apoE-/- mice were stained with Sudan IV using either in vivo perfusion or traditional in vitro enface staining techniques. Histological sections of aortic root and hearts were embedded in tissue freezing medium and cut with a cryostat, then stained with Oil Red O. The calculated aortic root area based on the aortic root circumference was used to reduce measurement errors. Results The in vitro en face staining can stain all fat, which include the adventitial tissue around aorta. However the in vivo perfusion staining can specifically stain the fatty deposition inside of aorta. Both entire aorta and aortic root section staining showed that there was a highly significant increase in fatty deposition in the aortas of the genetic modified mice. Although all mice genetic background was same, the apoE-/- mice had larger atherosclerotic lesions than ldlr-/- mice. Conclusions The new in vivo peffusion method is more accurate than the in vitro en face method. The combination of these macro and microscopic techniques overcomes the shortcomings of the earlier published methods which are generally limited to the measurement of fatty red staining areas only, neglecting non-specific adventitial fat staining around aorta and aortic root section tissue distortion.展开更多
Both NOD2 (CARD15) alleles aremutated in roughly 15%of patients with Crohn’s disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (...Both NOD2 (CARD15) alleles aremutated in roughly 15%of patients with Crohn’s disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFαor interleukin 1β, but strong interleukin-8 secretion. MDP also substantially upregulated sec retion of TNFαand interleukin 1βinduced by toll-like receptor ligands. These effects were abolished by the most common Crohn’s NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn’s disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NO D2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.展开更多
文摘The FOXO3a and FOXM1 forkhead transcription factors are key players in cancer initiation,progression,and drug resistance.Recent research shows that FOXM1 is a direct transcriptional target of FOXO3a,a vital downstream effector of the PI3K-AKT-FOXO signaling cascade.In addition,FOXM1 and FOXO3a also antagonize each other's activity by competitively binding to the same target genes,which are involved in chemotherapeutic drug sensitivity and resistance.Understanding the role and regulation of the FOXO-FOXM1 axis will provide insight into chemotherapeutic drug action and resistance in patients,and help to identify novel therapeutic approaches as well as diagnostic and predictive biomarkers.
文摘Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogram-ming, reversing the epigenetic configuration of differ-entiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mecha-nisms underlying these roles.
基金Grants from the Novo Nordisk UK Research Foundation (supporting S.R.M)Pfizer Global Research and Development (Sandwich, UK)the British Medical Research Council and the United Kingdom Department of Health Research and Development Initiative
文摘Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo 1H MRS is a fast, safe, non-invasive method forthe quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.
基金Supported by NIHR Biomedical Research Centre funding scheme
文摘Primary liver cancer is amongst the commonest tumors worldwide,particularly in parts of the developing world,and is increasing in incidence. Over the past three decades,surgical hepatic resection has evolved from a high risk,resource intensive procedure with limited application,to a safe and commonly performed operation with a range of indications. This article reviews the approach to surgical resection for malignancies such as hepatocellular cancer,metastatic liver de-posits and neuroendocrine tumors. Survival data after resection is also reviewed,as well as indications for curative resection.
基金Supported by The NIHR Biomedical Research Centre funding scheme and the following for authors’ funding and supportAIG is funded by a scholarship from the Egyptian Government+5 种基金SAK is supported by a grant from the Higher Education Funding Council for England (HEFCE)SDTR is funded by grants from the British Medical Research Council (MRC), London, United KingdomThe British Engineering, Physics and Science Research Council (EPSRC), Swindon, United KingdomThe Alan Morement Memorial Fund AMMF, Essex, United KingdomBroad Foundation, Los Angeles, United StatesPfizer Global Research and Development Inc, Sandwich, United Kingdom and GlaxoSmithKline, Ware, United Kingdom
文摘Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.
基金Supported by the Hammersmith Hospital Trustees Research Committee, the Medical Research Council, JEOL (UK) Ltd., Phil- ips Medical Systems and the Higher Education Funding Council for England
文摘Nuclear magnetic resonance spectroscopy allows the study of cellular biochemistry and metabolism, both in the whole body in vivo and at higher magnetic field strengths in vitro. Since the technique is non-invasive and non-selective, magnetic resonance spectroscopy methodologies have been widely applied in biochemistry and medicine. In vitro magnetic resonance spectroscopy studies of cells, body fluids and tissues have been used in medical biochemistry to investigate pathophysiologi- cal processes and more recently, the technique has been used by physicians to determine disease abnormalities in vivo. This highlighted topic illustrates the potential of in vitro magnetic resonance spectroscopy in studying the hepatobiliary system. The role of in vitro proton and phosphorus magnetic resonance spectroscopy in the study of malignant and non-malignant liver disease and bile composition studies are discussed, particularly with reference to correlative in vivo whole-body magnetic resonance spectroscopy applications. In summary, magnetic resonance spectroscopy techniques can provide non-invasive biochemical information on disease severity and pointers to underlying pathophysiological processes. Magnetic resonance spectroscopy holds potential promise as a screening tool for disease biomarkers, as well as assessing therapeutic response.
基金Supported by Research Grant from the British Medical Research Council, Pfizer Global Research (Sandwich, UK) and the United Kingdom Department of Health Research and Development Fund. SM is funded by a clinical and research fellowship from the Société des Radiologistes de l’Hpital St-Franois d’Assise, Québec, Canada
文摘Ultrasound (US) is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of specific contrast media and the development of specialized imaging techniques. Ultrasound now can fully characterise the enhancement pattern of hepatic lesions, similar to that achieved with contrast enhanced multiphasic computed tomography (CT) and magnetic resonance imaging (MRI). US contrast agents are safe, well-tolerated and have very few contraindications. Furthermore, real-time evaluation of the vascularity of focal liver lesions has become possible with the use of the newer microbubble contrast agents. This article reviews the enhancement pattern of the most frequent liver lesions seen, using the second generation US contrast media. The common pitfalls for each type of lesion are discussed. The recent developments in US contrast media and specific imaging techniques have been a major advance and this technique, in view of the intrinsic advantages of US, will undoubtedly gain popularity in the years to come.
文摘Haemangiomas are the most common solitary benign neoplasm of the liver with an incidence ranging from 5% to 20%. Although usually small and asymptomatic, they may reach considerable proportions and rarely give rise to life-threatening complications. Surgical intervention is required for incapacitating symptoms, established complications, and diagnostic uncertainty. The resection of haemangiomas demands meticulous surgical technique, owing to their high vascularity and the concomitant risk of intra-operative haemorrhage. Laparoscopic resection of giant haemangiomas is even more challenging, and has only been reported twice. We here report the case of a giant 10 cm liver haemangioma which was successfully resected laparoscopically using the laparoscopic HabibTM 4×, a bipolar radiofrequency device, without clamping major vessels and with minimal blood loss. Transfusion of blood or blood products was not required. The patient had an uneventful recovery and was asymptomatic at 7-mo follow-up.
文摘AIM: To study costs of laparoscopic and open liver and pancreatic resections, all the compiled data from available observational studies were systematically reviewed.
基金the United Kingdom Department of Health, British Medical Research Council, Grant No. G99000178 and the United Kingdom National Health Service Research and Development Initiative
文摘Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This article examines the various assessment methods currently available from gold standard liver biopsy to serological markers and imaging. Ultrasound is one of the most widely used imaging modalities in clinical practice and is already a first-line diagnostic tool for liver disease. Microbubble ultrasound contrast agents allow higher resolution images to be obtained and functional assessments of microvascular change to be carried out. The role of these agents in quantifying the state of hepatic injury is discussed as a viable method of determining the stage and grade of liver disease in patients with hepatitis C. Although currently confined to specialist centres, the availability of microbubble contrast-enhanced ultrasound will inevitably increase in the clinical setting.
基金Supported by Ministerio de Ciencia E Innovación-Bernat Soria-Innpacto Proyect,No.IPT-2011-1615-900000Instituto de Salud Carlos III,Gobierno de Espana-Bernat Soria,No.TERCEL RD06/0010/0025+1 种基金Consejeria de Salud Junta de Andalucia-Francisco Javier Bedoya Bergua,No.PI-0105-2010Consejeria de Economia Innovación Ciencia y Empleo-Junta de Andalucia-Francisco Javier Bedoya,No.CTS-7127/2011.
文摘Mitochondrial dysfunction and endoplasmic reticulum stress(ERS)are global processes that are interrelated and regulated by several stress factors.Nitric oxide(NO)is a multifunctional biomolecule with many varieties of physiological and pathological functions,such as the regulation of cytochrome c inhibition and activation of the immune response,ERS and DNA damage;these actions are dose-dependent.It has been reported that in embryonic stem cells,NO has a dual role,controlling differentiation,survival and pluripotency,but the molecular mechanisms by which it modulates these functions are not yet known.Low levels of NO maintain pluripotency and induce mitochondrial biogenesis.It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca^(2+)flux that induce ERS.Thus,at high concentrations,NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines.Nevertheless,many studies have demonstratedthe need for physiological levels of NO for a proper ERS response.In this review,we stress the importance of the relationships between NO levels,ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.
文摘Objectives: To report the spectrum of brain magnetic resonance imaging findings in 13 patients with congenital muscular dystrophy and FKRP gene mutations and to explore possible genotype-phenotype correlations. Design: We retrospectively reviewed brain magnetic resonance imaging in patients with congenital muscular dystrophy and FKRP gene mutations. Patients: Thirteen patients with congenital muscular dystrophy and mutations in the FKRP gene. Results: Five of the 13 patients had the typical phenotype originally described for congenital muscular dystrophy (MDC1C) with normal intelligence and normal brain magnetic resonance imaging while 3 other patients had isolated cerebellar cysts and mental retardation without any other sign of posterior fossa of supratentorial abnormalities. In the remaining 5 patients cerebellar cysts were associated with structural brain changes involving the posterior fossa and the cortex, ranging from focal unilateral periventricular nodular heterotopia to marked cerebellar dysplasia and pontine hypoplasia. In 2 of these 5 patients the severity and distribution of changes resembled muscle-eye-brain disease in 1 patient who had mild Walker-Warburg syndr ome. The distribution of FKRP gene mutations identified in this group of patients did not reveal any obvious association with the severity of central nervous system involvement. Conclusions: The severity of central nervous system involvement observed in our patients in contrast broadly reflected the severity of the disruption of α-dystroglycan glycosylation. In particular, dystroglycan expression was almost absent in the patients with muscle-eye-brain diseaselike phenotype and less severely reduced in the patients with congenital muscular dystrophy (MDC1C) with or without cerebellar cysts. This study further highlights the central role that dystroglycan has in neuronal migration.
文摘Dear Editor,Varicocele is a common cause of male infertility,but in the course of a diagnostic infertility workup,other underlying problems are often found.Up to two-thirds of patients with nonidiopathic male infertility have at least two possible etiologies.
文摘Background: Kisspeptin has been demonstrated to affect the attainment of puberty in multiple species, presumably through its actions on GnRH and LH. It has previously been found there is an increase in expression of hypothalamic in the rat and the monkey coincident with puberty. Whether a similar phenomenon occurs in the pig remains to be determined. The objectives of the current experiments were to determine 1) Plasma concentrations of estradiol-17β;2) Anterior pituitary gland concentrations of LH, IGF-I, kisspeptin, and anterior pituitary gland expression of LH-β and GnRH receptor;3) Mediobasal hypothalamus expression of Kiss1 and concentrations of kisspeptin during the peripubertal period in the gilt. Methods: Two experiments were performed, each with 25 crossbred gilts (151 d, 105 kg). Gilts were relocated and exposed to a mature boar beginning on d 1 and continuing throughout the experiments to naturally induce puberty. Gilts that stood immobile within 24 hours of slaughter were considered to have attained puberty. Plasma samples were collected on d 1, 3, and 7 of the first experiment and d 2, 4, 6, and 8 of the second experiment. Gilts were slaughtered on d 7 (experiment 1) or d 8 (experiment 2), when mediobasal hypothalamus (MBH), anterior pituitary glands (AP), and blood were collected. Relative expression of MBH Kiss1 and β-actin and AP GnRH receptor, LH-β, was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Hypothalamic and AP content of kisspeptin were determined by RIA and differences were determined using the GLIMMIX procedure of SAS. Results: Relative expression of Kiss1 was increased (P = 0.005) 2.2 fold in the gilts that had attained puberty in the first experiment, however, those that had attained puberty in the second were not different (P > 0.05) from gilts that had not. Relative expression of GnRH receptor was not different (P > 0.05) between treatments in both experiments. Relative expression of LH-β tended to be decreased (P = 0.09) 0.80 fold in gilts that attained puberty in the first experiment but was not different (P > 0.05) in gilts that attained puberty in the second experiment. AP concentrations of LH were not different (P > 0.05) between treatments in the first experiment and were decreased (P = 0.01) in gilts that attained puberty in the second experiment. AP concentrations of kisspeptin were not different (P > 0.05) in the first experiment but were increased (P = 0.04) in gilts that had attained puberty in the second experiment. MBH concentrations of kisspeptin were increased (P = 0.03) in gilts that had attained puberty in the first experiment but were not different (P > 0.05) between treatments in the second experiment. Conclusions: These data further support the role that MBH expression of Kiss1 and concentrations of kisspeptin and AP concentrations of kisspeptin fluctuate during the peripubertal period and may play a role in the attainment of puberty in the gilt.
文摘<span style="font-family:Verdana;">Kisspeptin has been demonstrated to affect reproductive cyclicity and the attainment of puberty in multiple species, presumably through its actions on gonadotropin releasing hormone and luteinizing hormone. Kisspeptin administration causes increased plasma concentrations of LH in pigs, sheep, and rats. The objective of this experiment was to evaluate changes in the hypothalamic kisspeptin system throughout the estrous cycle in gilts. Estrus was synchronized in forty crossbred gilts (191 d, 121 kg) and estrus detection was performed by exposing gilts to a mature boar. The first day gilts stood immobile was denoted d 1 of the estrous cycle. Blood samples were collected via jugular venipuncture on d 1, 4, 7, 9, 14, 16, and 19 of the estrous cycle. Ten animals were slaughtered on d 1, 9, 14, and 21 of the estrous cycle when medial basal hypothalami, anterior pituitary glands, and blood were collected. Relative expression of hypothalamic kisspeptin (KISS1), kisspeptin receptor (KISS1R), estrogen receptors-a, anterior pituitary gland GnRH receptor, </span><i><span style="font-family:Verdana;">β</span></i><span style="font-family:Verdana;">-actin</span><span style="font-family:Verdana;" "="">,</span><span style="font-family:;" "=""><span style="font-family:Verdana;"> and GAPDH was determined using real-time reverse transcriptase PCR. Fold changes in relative expression were determined using the Relative Expression Software Tool. Relative expression of KISS1 was increased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.006) 3.2 fold on d 1 versus d 21 and 2.3 fold (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.003) on d 9 versus d 21 of the estrous cycle, but was not different (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 0.05) among the remaining days of the estrous cycle. Relative expression of estrogen receptor-b was decreased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.05) 0.8 fold on d 9 versus d 21 and (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> = 0.005) 0.7 fold on d 14 versus d 21, but was not different (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 0.05) among the remaining days. Relative expression of anterior pituitary gland GnRH receptor was increased (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> < 0.01) on d 1 and 21 versus d 9 and 14. These data support the notion that medial basal hypothalamic expression of KISS1 changes throughout the estrous cycle and may influence reproductive cyclicity in the gilt.</span></span>
基金The study was pre-registered with the Prospective Register of Systematic Reviews,PROSPERO identification code:CRD42018090367.
文摘Objective:Bariatric surgery has been shown to be an effective method of treatment for obstructive sleep apnea(OSA)with long-term benefits,however,the mechanisms of action and the optimum operative procedure remains unclear.The aim of this systemic review was to compare the efficacy of laparoscopic sleeve gastrectomy(LSG)and Roux-en-Y gastric bypass(RYGB)in resolving OSA.Methods:A comprehensive search of MEDLINE,Pubmed,Embase,and OVID was performed.Studies that reported OSA resolution in obese patients with BMI>30 kg/m2 were included in the study.RCTs,comparative prospective and matched cohort studies comparing RYGB with LSG were considered for this study.Results:Five studies(309 participants)were included:4 cohort studies and 1 RCT;all with low risk of bias.At 12 months follow-up,there was a trend towards improved resolution of OSA with LSG(OR 0.47,95%CI[0.20 to 1.06];p=0.07)when compared to RYGB.In contrast,there was a trend to poorer weight loss in the LSG group(SMD 3.83,95%CI[-1.82 to 9.48];p=0.18).Similarly,at 36 months follow-up,there was a trend towards better resolution of OSA with LSG(OR 0.52,95%CI[0.16 to 1.71];p=0.28)and a significantly poorer weight loss in LSG when compared to RYGB(SMD 8.25,95%CI[2.91 to 13.58];p=0.002).Conclusion:Despite poorer weight loss following LSG,there is a trend towards increased resolution of sleep apnea post-LSG.These findings suggest the possibility of weight loss independent factors causing OSA resolution,which should be further investigated.Registration:PROSPERO:CRD42018090367.
基金Supported by A grant from the Department of Health,Basque Government,Spain,Exp.No.2007111002
文摘Giardia is an enteric protozoan that infects a wide range of vertebrate hosts, being considered a major causative agent of gastrointestinal disease in humans in both developing and developed countries. Giardia infection has also a significant impact on livestock health, causing diarrhoea and resulting in significant economic lost. Transmission is either direct, through the faecal-oral route, or indirect, through ingestion of contaminated water or food. In this article, we review current knowledge about the epidemiology of giardiasis in different populations in Spain, including humans, livestock, companion animals, and wildlife. Environmental contamination of surface waters and raw foods by Giardia cysts is also addressed. Special relevance has been given to the data available on the molecular characterization of the Giardia isolates obtained from clinical and environmental samples, as determining thespecies/assemblages and subassemblages involved is essential for accurately identifying the parasite and assessing zoonotic transmission. The public health significance of these findings has also been thoroughly discussed.
基金supported by the Hong Kong WangKuan Cheng Foundation GrantBritish Heart Foundation
文摘Objectives To develop a simple, accurate and reproducible method, which combines macro and histopathological techniques for determining the degree of lipid deposition in genetically modified mice. Method The entire aortas from C57BL/6, ldlr-/- and apoE-/- mice were stained with Sudan IV using either in vivo perfusion or traditional in vitro enface staining techniques. Histological sections of aortic root and hearts were embedded in tissue freezing medium and cut with a cryostat, then stained with Oil Red O. The calculated aortic root area based on the aortic root circumference was used to reduce measurement errors. Results The in vitro en face staining can stain all fat, which include the adventitial tissue around aorta. However the in vivo perfusion staining can specifically stain the fatty deposition inside of aorta. Both entire aorta and aortic root section staining showed that there was a highly significant increase in fatty deposition in the aortas of the genetic modified mice. Although all mice genetic background was same, the apoE-/- mice had larger atherosclerotic lesions than ldlr-/- mice. Conclusions The new in vivo peffusion method is more accurate than the in vitro en face method. The combination of these macro and microscopic techniques overcomes the shortcomings of the earlier published methods which are generally limited to the measurement of fatty red staining areas only, neglecting non-specific adventitial fat staining around aorta and aortic root section tissue distortion.
文摘Both NOD2 (CARD15) alleles aremutated in roughly 15%of patients with Crohn’s disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFαor interleukin 1β, but strong interleukin-8 secretion. MDP also substantially upregulated sec retion of TNFαand interleukin 1βinduced by toll-like receptor ligands. These effects were abolished by the most common Crohn’s NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn’s disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NO D2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.
