Molecular adsorbent recirculating system as artificial support therapy for liver failure: a meta-analysis

Molecular Adsorbent Recirculating System (MARS) is an artificial liver support system that has been developed for patients with liver failure until the liver regains function or as a bridge to transplantation. We conducted a meta-analysis to examine the efficacy of this promising therapy. We searched MEDLINE, EMBASE, and the Cochrane Registry of Controlled Trials databases, and abstracts from the proceedings of several scientific meetings. Patients with acute, acute on chronic, and hyperacute liver failure were included and we compared MARS with standard medical therapy. Randomized and nonrandomized controlled trials were included and Molecular Adsorbent Recirculating System was the intervention used. We evaluated net change in total bilirubin levels, improvement in hepatic encephalopathy and mortality. Nine randomized controlled trials and one nonrandomized controlled study met criteria and were included. By meta-analysis, MARS resulted in a significant decrease in total bilirubin levels (net change -7.0 mg/dl; 95% CI -10.4, -3.7; p < 0.001) and in an improvement in the West-Haven grade of hepatic encephalopathy (odds ratio [OR] 3.0; 95% CI 1.9, 5.0; p < 0.001). There was no beneficial effect on mortality (OR 0.91; 95% CI 0.64, 1.31; p = 0.62). The limitations of this study include a small sample size, an inability to blind with significant heterogeneity among studies, and variable definitions of liver failure. The Molecular Adsorbent Recirculating System is associated with a significant improvement in total bilirubin levels and hepatic encephalopathy but has no impact on survival. Large studies are required to assess the merit of this promising therapy on patient-centered outcomes.     

Changes in serum electrolytes during treatment of patients in liver failure with molecular adsorbent recirculating system

PURPOSE: To study the effect of MARS on serum electrolytes during liver failure. DESIGN: Twenty-three patients admitted to a quaternary health care facility from September 2000 to May 2002, 22 adults and 1 child, 11 males (48%) and 12 females (52%), age 15-70 (median 53), treated with MARS for: 12 acute-on-chronic liver failure (52%); 4 fulminant hepatic failure (17%); 3 intractable pruritus (13%); 2 primary-non-function (9%); 2 following major liver resection (9%). PROCEDURES: Sodium, potassium, chloride, phosphorus, calcium, and magnesium were measured in the serum, ultrafiltrate and albumin circuit before and after MARS. STATISTICAL METHODS: A comparison of electrolyte concentrations, before and after MARS, was performed using a paired t test. MAIN FINDINGS: Serum electrolyte concentrations before and after MARS, while statistically significant in some cases, were very small, and of no clinical relevance. CONCLUSION: MARS exchanges potassium, chloride, calcium, and magnesium by ultrafiltration; sodium by the albumin dialysis.     

MARS in the treatment of liver failure: controversies and evidence

Molecular Adsorbent Recirculation System (MARS) is a form of extracorporeal detoxification system used as an artificial liver support system. Numerous studies have been published on the topic, with the majority of them describing the capability of MARS in removing albumin-bound toxins and improving systemic hemodynamics. Whether such improvement could be translated into survival benefit is still uncertain, given the paucity of randomized controlled trials available. The outcome of patients receiving MARS treatment is difficult to analyze because liver failure patients constitute a heterogeneous population and different subgroups carry different prognoses. An evidence-based recommendation on the timing of MARS initiation is not available and currently MARS is usually commenced for hyperbilirubinemia or presence of complications of liver failure. MARS is in general a safe procedure, but there are still potential complications that need to be cautioned, along with various operative issues that are worth attention. The future prospects of MARS would rely on the completion of adequately powered randomized controlled trials.     

应用MARS人工肝治疗急慢性重型肝炎临床研究

探讨分子吸附再循环系统(MARS)人工肝支持系统治疗重型肝炎的疗效和安全性。方法7例重型肝炎患者在内科综合治疗同时,加用MARS人工肝治疗。MARS人工肝治疗每次持续6～8h。结果7例重型肝炎患者在MARS治疗后,血总胆红素和总胆酸分别由(410.90±256.99)μmol/L和(107.37±69.78)μmol/L降至(310.60±88.97)μmol/L和(60.96±36.27)μmol/L(P<0.001);肌苷和尿素分别由(234.43±90.83)mmol/L和(12.64±5.29)mmol/L降至(93.29±45.27)mmol/L和(6.59±3.73mmol/L(P<0.05);凝血酶原时间(PT)和活化部分凝血酶时间(APTT)分别由(26.81±)13.01s)和(57.54±18.44)s缩短至(17.98±4.52)s和(40.57±11.14)s(P<0.05MARS治疗前后患者血K 、Na 、白细胞和);血小板无显著改变(P>0.05);在MARS治疗期间患者血压、脉搏稳定。4例合并肝肾综合征(HRS)患者中,2例经MARS治疗病情好转,肾功能改善。结论MARS人工肝支持系统是治疗重型肝炎及合并HRS有效和安全的方法。     

Rh血型系统的分子遗传学及其医学应用

Rh血型系统是人类较为复杂和重要的血型系统。它有两个同源结构基因串联排列在1p34.3-36.1，编码的Rh蛋白为有2个跨膜域的红细胞膜蛋白。Rh抗原有很多变异体；RhD阴性个体存在3种遗传多态性。Rh血型系统在临床输血及新生儿溶血病（hemolytic disease of the newborn,HDN)中意义重大，可利用PCR进行Rh基因分型方法对胎儿进行产前诊断，但此方法仍有一定缺陷。需要对Rh血型系统进行更深入的认识，以解决这一问题。     

Thoracolumbosacral laminectomy in achondroplasia: long-term results in 22 patients

Neurologic problems caused by vertebral stenosis in the thoracolumbosacral (TLS) region are common in achondroplasia. Surgical decompression by means of laminectomy is recommended often, but its long-term results have not been assessed. We reviewed the clinical history of 22 achondroplastic patients who had at least one TLS laminectomy performed before 1981. Symptoms predated the first TLS laminectomy by a mean of 2.3 years (range 0.1-17 years). Preoperatively, 91% of patients had motor function impairment, 86% had sensory dysfunction, 86% had neurogenic claudication, 77% had radicular pain, 59% had symptomatic bladder dysfunction, and 32% had fecal incontinence. Only upper motor neurons were affected in 45%, only lower motor neurons in 27%, and both in 27%. Follow-up after the first TLS laminectomy averaged 8 years. Of the 20 patients who initially improved neurologically, 12 had functional improvement for more than 5 years. However, 11 of these 12 subsequently regressed and 10 had additional laminectomies. Long-term neurologic and functional improvement was associated with both a short duration of symptoms preoperatively and absence of cervical stenosis. Because of hypertrophic scarring, 9 patients developed compression at the site of the initial TLS laminectomy and required re-operation 6.4 years (range 1-11 years) later. We conclude that TLS laminectomy is an effective treatment for spinal stenosis if performed early in the course of the neurologic syndrome. However, some patients have, or later develop, compression adjacent to the myelographic site of stenosis, and some develop hypertrophic scarring at the site of initial decompression. We therefore suggest that the first TLS laminectomy extend (1) 3 levels cephalad to the myelographic block, (2) at least to S2, and (3) laterally at least to the facets.     

Significant decrease in dialysate albumin concentration during molecular adsorbent recirculating system (M.A.R.S.) therapy

AIM: The molecular adsorbent recirculating system (M.A.R.S.) is widely used as liver support therapy in patients with hepatic dysfunction. The goal of this study was to measure changes in dialysate albumin and bilirubin concentrations during clinical MARS treatments. METHODS: Eight patients with acute liver dysfunction and hyperbilirubinemia were enrolled in this study. Five of them received a total of 10 treatments with MARS, in which 600 mL of 20% human albumin was used as dialysate, continuously regenerated by two adsorbent columns in the circuit. Three patients received 4 treatments of a modified MARS, in which the two adsorbent columns were bypassed in the first course for 4 h, and then connected to the circuit in the second course for another 4 h. The total, conjugated and unconjugated bilirubin (TB, CB, UCB) and albumin concentrations in serum and albumin dialysate were dynamically measured, and the adsorbent column inlet pressures were recorded during each session. In one session, dialysate albumin levels were measured during the priming process, at the time points prior to the priming process, immediately after priming, and at the end of the treatment. RESULTS: During MARS therapies, the reduction ratio of serum TB, CB and UCB was 26.6+/-9.0%, 29.5+/-9.6% and 14.8+/-12.3%, respectively. The molar ratio of TB/albumin in serum was approximately 20-fold higher than dialysate at all time points. A significant albumin concentration decrease from baseline in the dialysate was found (mean+/-SD, 34.6+/-16.6%). For the first four hours of modified treatments, in which only albumin dialysis without albumin regeneration by adsorbent columns was performed, the dialysate albumin decrease was substantially smaller (mean, 8.3+/-1.5%). After switching to standard MARS, there was a further decrease in the dialysate albumin concentration of 35.1+/-14.5%. In one session, dialysate albumin concentrations were measured during the priming process, and levels decreased from 196.9 g/L to 144.4 g/L. Adsorber inlet pressure increased from 40+/-10 mmHg at the start of priming to 150+/-50 mmHg at the end of priming, and further increased to 340+/-100 mmHg at the end of treatment. CONCLUSION: There is a significant reduction in dialysate albumin concentration during MARS therapy. Binding of albumin to the adsorbent columns used for albumin regeneration is largely responsible for this decrease.     

Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

IntroductionAminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1.We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms.ResultsThe first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature.All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia.Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations.ConclusionPatients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.     

Liver histology as predictor of outcome in patients with acute-on-chronic liver failure (ACLF)

There is paucity of literature on liver histological spectrum of acute-on-chronic liver failure (ACLF). The aims of this study are to (a) to characterize the liver histological features in ACLF, (b) to correlate histological parameters with prognosis, and (c) to investigate whether etiology influences prognosis. We retrospectively studied liver biopsies of patients with ACLF. The histological findings were correlated with the clinical outcome. Fifty cases (median age, 39 years [10–69 years]; M/F, 3:1) were included. Etiology of acute insult was viral or alcohol in majority of the cases. Twenty-five patients survived (good outcome, 50%) and 25 died (poor outcome, 50%). On a univariate analysis, the outcome correlated with fibrosis, ballooning, eosinophilic degeneration, ductular proliferation, pericellular fibrosis, Mallory’s hyaline, foci of confluent necrosis and/or bridging necrosis (CN/BN), cholestasis, apoptosis (present), and parenchyma left. However, on a multivariate analysis, only fibrosis, ballooning, ductular proliferation, apoptosis, and parenchyma left were found to be independently associated with outcome. Two distinct patterns of liver histology were observed: pattern I, observed in cases with poor outcome, showing marked ductular proliferation, coarse inspissated ductular bile plugs, eosinophilic degeneration of hepatocytes, foci of CN/BN, higher apoptosis, pericellular fibrosis, Mallory’s hyaline, and higher stage of fibrosis. Pattern II is seen in cases with good outcome, show prominent hepatocyte ballooning with lesser parenchymal involvement by fibrosis and necrosis. Histological features of liver biopsy are: extent of fibrosis, ballooning, ductular proliferation, apoptosis, and lesser degree of parenchymal replacement by fibrosis or necrosis which correlates with the outcome in patients with ACLF. Two distinct patterns of liver histology are seen which help in prognostication.     

Biochemical assessment and clinical evaluation of a bilirubin adsorbent column (BR-350) in critically ill patients with intractable jaundice.

We investigated the efficacy of an anion-exchange adsorbent column (ASAHI BR-350, DIAMED) for removal of bilirubin and bile acids in five patients with intractable jaundice of various origin. Four litres of plasma were separated by membrane plasma separation (Plasmaflow OP-05) at a rate of 22.5 ml/min. The plasma was then perfused through an anion exchange adsorbent and returned to the venous blood line of the plasma separation. In some of the patients this procedure was combined with regular hemodialysis treatment. The concentration of total bilirubin was cut by 31 to 60%; total bile acids were reduced by 20 to 74%. Three patients recovered and had a favourable outcome. Two patients died despite the bilirubin adsorption treatment. The effects of the adsorbent column on specific blood parameters, including the coagulation system, were measured. Our data suggest that bilirubin adsorption should be examined further as a treatment for critically ill patients with intractable jaundice.     

Serum lipoprotein (a) levels in chronic renal failure and liver cirrhosis patients. Relationship with atherosclerosis

This study was carried out to investigate the relationship between lipoprotein (a) levels and the development of atherosclerosis in chronic renal failure (CRF) patients with the possible role of the liver. Serum Lp (a) levels were measured in samples from 20 CRF patients on hemodialysis (HD), 20 liver cirrhosis (LC) patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Renal function (blood urea nitrogen (BUN) and creatinine), hepatic function (transaminases (ALT and AST), alkaline phosphatase (ALP) and total bilirubin) investigations and serum cholesterol were carried out for all the subjects enrolled in this study. Serum Lp (a) concentration in CRF patients without LC was 87.25 +/- 6.17 mg/dl, which was significantly higher than all the investigated groups (P < 0.001). Lp (a) concentration in patients with both CRF and LC was 24.65 +/- 1.98 mg/dl, which was not significantly different from the controls, but was significantly higher than that in the subjects with LC only (P < 0.001) where the latter group had significantly low Lp (a) values (11.1 +/- 0.99) relative to all the other groups (P < 0.001). Lp (a) correlated positively with cholesterol in all groups except the LC subjects, but did not correlate with age, or renal function in both CRF groups.     

The michill adjective rating scale (MARS): Scoring procedures and normative data

The Michill Adjective Rating Scale (MARS) measures four relatively independent factors (unhappiness, extraversion, self-assertiveness, and productive persistence) and has been used to secure ratings of self and other significant individuals from both normal and maladjusted persons. Procedures for administering and scoring and the normative data (means and standard deviations), based on high school students, college undergraduates, and obese adults, are presented here in order to facilitate the experimental use of MARS in clinical and psychosocial research.     

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.     

严重生精功能障碍患者细胞和分子遗传学检查

目的检测严重生精功能障碍患者外周血染色体及Y染色体微缺失,探讨Y染色体微缺失的遗传机制,为拟行ICSI(intracytoplasmic sperm injection,ICSI)技术助孕的患者提供遗传咨询。方法按常规方法分析严重生精功能障碍患者的外周血淋巴细胞核型,对核型正常的患者,用多重PCR技术对Y染色体AZF(azoospermua fctor,AZF)所在区域的 15个序列标签位点(sequence tag site,STS)进行扩增,应用琼脂糖凝胶电泳分离扩增产物,对有AZF缺失的患者,随访其父亲的生育及AZF缺失情况。结果 71例无精子症患者中有25例染色体核型异常,异常率35．1％,1例核型为46,XY (小Y);75例严重少精子症患者中有4例46,XY(小Y);45例染色体核型正常的严重生精功能障碍患者,14例发生 AZF缺失(31．11％)。严重生精功能障碍患者总遗传缺陷发生率26．7％。所有AZF缺失患者父亲平均生育4．0个子女,其中有5例AZF缺失患者的父亲接受AZF检测,均无缺失。结论 1．染色体异常和AZF的缺失是引起无精子和严重少精子并造成男性不育的重要原因之一。AZF缺失可能并非有父亲遗传而来,其遗传机制尚有待进一步探讨。2．ICSI助孕前,夫妇双方须行遗传学检查以避免遗传缺陷后代的出生。     

Molecular and genetic aspects of heart failure in diabetic patients

This article deals with peculiarities of development and clinical course of heart failure (HF) in diabetic patients, influence of diabetic cardiopathy on HF formation., role of genetic predictors of diabetes mellitus (DM) and HF formation, also the importance of treatment response predictors, the significance of a more "personalized" exposure in order to optimize treatment. The role of stationary and dynamic genomics was analyzed, especially molecular visualization that allows the earliest possible intervention. The article also includes examples of molecular visualization use in diagnosis of myocardial dysfunction, disease monitoring, and treatment efficacy assessment. Authors give an analysis of targeted treatment methods on the example of targeted delivery of medications to the target-organ (myocard). Discuss means of anti-ischemic myocardial protection, perspectives of metformin use in order to enhance efficacy of myocardial ischemic pre- and postconditioning mechanisms. Presented perspectives of study of molecular and genetic mechanisms involved in the pathogenesis of HF in diabetic patients, in particular, study of key biological features of stem cells, cell interactions, stem cell plasticity (in vitro direction of differentiation) and their paracrine function evaluation. Given information about identification of genes with partly altered expression due to chronic exposure of mesenchymal stem cells to the high concentration of glucose, and upon decreased ability of mesenchymal stem cells of proangiogenic factors with simultaneous increase of inflammatory markers production (IL8). In whole this article reviews modern state of HF in diabetic patients development mechanisms study with the use of molecular and genetic technologies, and of perspectives of development of this area.     

Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.