The importance of AST / ALT rate in nonalcoholic steatohepatitis diagnosis

BACKGROUND/AIMS: There is a histologic similarity between nonalcoholic steatohepatitis and alcoholic liver disease and in some cases differential diagnosis may be difficult, since some patients do not report abusive alcohol consumption. OBJECTIVE: Evaluating the usefulness of setting the rate AST/ALT for the differential diagnosis of nonalcoholic steatohepatitis and alcoholic liver disease. PATIENTS AND METHODS: Twenty nine obese patients with nonalcoholic steatohepatitis were compared with 28 patients with alcoholic liver disease. The diagnosis of nonalcoholic steatohepatitis was made after exclusion of other causes of liver disease and by histologic findings of, at least, macrovesicular steatosis and hepatocellular necrosis. RESULTS: In patients with nonalcoholic steatohepatitis the medium AST value was 52.3 +/- 21.2 U/L and ALT of 90.1 +/- 37.9 U/L, being the AST/ALT rate lower than 1 in all patients. In patients with alcoholic liver disease the medium AST value was 140 +/- 82.5 U/L and ALT was 50.6 +/- 40.3 U/L. The rate was higher than 1 in all cases and higher than 2 in 24 (85.7%), being statistically significant when compared with patients with nonalcoholic steatohepatitis. CONCLUSION: The AST/ALT rate seems to be useful in the differential diagnosis of liver diseases, while lower than 1 is highly suggestive of nonalcoholic steatohepatitis.     

Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets

The effect of melatonin (0.1 microM) on freshly isolated islets from adult rats was investigated. Melatonin caused a marked decrease of insulin secretion by islets in response to glucose. The mechanism involved was then examined. Melatonin did not interfere with glucose metabolism as indicated by the measurement of glucose oxidation. However, the content of the protein kinase A (PKA) catalytic alpha-subunit was significantly decreased in islets exposed to melatonin for 1 hr in the presence of 8.3 mM glucose, whereas that of the protein kinase C (PKC) alpha-subunit remained unchanged. Melatonin also inhibited forskolin-induced insulin secretion, a well known activator of adenylate cyclase (AC) activity. This may explain the low content of insulin found in islets incubated in the presence of melatonin for 3 hr. In fact, 3',5' -cyclic adenosine monophosphate (cAMP), a product of AC activity, stimulates insulin synthesis. These findings led us to postulate that a down-regulation of the PKA signaling pathway may be the mechanism involved in the melatonin inhibition of the process of glucose-induced insulin secretion.     

The acid-labile subunit of human ternary insulin-like growth factor-binding protein complex in girls with central precocious puberty before and during gonadotropin-releasing hormone analog therapy

The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty. We studied serum ALS, free IGF-I, total IGF-I, IGFBP-3 levels and IGFBP-3 protease activity in 13 girls, aged 1.6-7.8 yr (mean, 5.9 +/- 2.2), diagnosed as having CPP before and after 6 and 12 months of GnRH analog (GnRHa) therapy. The ALS SD score before treatment was high (1.4 +/- 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 +/- 0.54 (P < 0.01) and -0.4 +/- 0.61 (P < 0.01), respectively]. Serum IGF-I and IGFBP-3 were also increased before treatment, but both of these factors remained elevated after 6 and 12 months of GnRH-A therapy [IGF-I SD score, 3.20 +/- 1.64, 2.92 +/- 1.82, and 3.68 +/- 1.94 (P = NS), respectively; IGFBP-3 SD score, 1.02 +/- 0.53, 0.94 +/- 0.68, and 1.22 +/- 0.87 (P = NS), respectively]. Serum free IGF-I levels and IGFBP-3 proteolytic activity did not vary significantly from their pretreatment values during GnRHa therapy. In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy.     

Differential change in left ventricular mass and regional wall thickness after cardiac resynchronization therapy for heart failure.

AIMS: LV reverse remodelling has been shown to be a favourable response after cardiac resynchronization therapy (CRT) in many clinical trials. This study investigated whether left ventricular (LV) reverse remodelling after CRT has any structural benefit, which include the improvement of LV mass or regional wall thickness. METHODS AND RESULTS: Fifty patients (66 +/- 11 years) receiving CRT were followed up for at least 3 months. Echocardiography with tissue Doppler imaging was performed serially before and at day 1 and 3 months after CRT. Although LV end-systolic volume (LVESV) was decreased at day 1 after CRT (141 +/- 74 vs. 129 +/- 71 cm(3), P < 0.001), further LV reverse remodelling was observed at 3 months (110 +/- 67 cm(3), P < 0.001 vs. day 1). LV ejection fraction increased at day 1 (26.5 +/- 9.3 vs. 28.5 +/- 9.1%, P < 0.005) and was further improved at 3 months (34.2 +/- 10.5%, P < 0.001 vs. day 1). However, reduction of LV mass (231 +/- 67 vs. 213 +/- 59 g, P < 0.001) and regional wall thickness was only observed at 3 months, but not at day 1. The improvement of LV mass correlated with the change in LVESV (r = 0.66, P < 0.001) and the baseline systolic asynchrony index (Ts-SD) (r = -0.52, P < 0.001). LV mass was only decreased significantly in responders of LV reverse remodelling (245 +/- 66 vs. 207 +/- 61 g, P < 0.001), but increased in non-responders (209 +/- 64 vs. 223 +/- 56 g, P = 0.02). Responders had significant decrease in thickness of all the four walls for -6 to -11% (all P < or =0.02), whereas non-responders had increased thickness in septal and lateral walls for +11% (both P < 0.05). CONCLUSION: The acute reduction in LV volume after CRT is mediated by haemodynamic and geometric benefits without actual changes in LV mass. However, at 3-month follow-up, reduction in LV mass and regional wall thickness was demonstrated, which represents structural reverse remodelling. Such benefit was only observed in volumetric responders but was worsened in non-responders.     

Immunological consequence of renal transplantation and immunosuppression. I. Alterations in human natural killer-cell activity

The role and activity of natural killer (NK) cells following renal transplantation remain unknown. To monitor NK activity, a⁵¹Cr release of K-562 targets in prednisone-and azathioprine-treated patients receiving renal allografts was utilized. In 18 patients in whom NK activity was measured prior to and after transplantation, a significant diminution in NK activity within 3 weeks following transplantation was demonstrated compared to pretransplant values (34.71 vs 12.20%, respectively;P<0.001). In 11 subjects who had NK activity assayed at various intervals after transplantation but not prior to allografting, mean NK values were markedly lower (mean, 14.2%) than those of normal volunteers or patients maintained on hemodialysis (P<0.001). The latter two control groups demonstrated no difference (P = NS) in mean NK activity (39.46 vs 35.82%, respectively). In 5 of the 29 patients evaluated with good long-term graft function (mean, 2.7 years), restitution of normal NK activity was demonstrated. In two patients with bacterial infections, NK activity increased from 39.29 to 51.7% and from 13.54 to 20.00%. After infection, these values were 35.3% in the former and 3.39% in the latter. Viral infection did not appear to affect NK activity significantly. NK activity was increased in only one of seven patients with documented rejection episodes. In three of such patients, NK activity declined significantly following pulse methylprednisolone therapy. These results indicate that (1) NK-cell activity significantly decreases immediately after transplantation, probably as a result of immunosuppressive therapy; (2) NK activity does not appear to be stimulated by the alloreactive rejection process; (3) NK activity may be augmented in the course of bacterial but not viral infections; and (4) long-term allograft survival may be associated with a restoration of NK-cell levels in certain recipients.     

Motor and parietal cortex stimulation for phantom limb pain and sensations

Limb amputation may lead to chronic painful sensations referred to the absent limb, ie phantom limb pain (PLP), which is likely subtended by maladaptive plasticity. The present study investigated whether transcranial direct current stimulation (tDCS), a noninvasive technique of brain stimulation that can modulate neuroplasticity, can reduce PLP. In 2 double-blind, sham-controlled experiments in subjects with unilateral lower or upper limb amputation, we measured the effects of a single session of tDCS (2 mA, 15 min) of the primary motor cortex (M1) and of the posterior parietal cortex (PPC) on PLP, stump pain, nonpainful phantom limb sensations and telescoping. Anodal tDCS of M1 induced a selective short-lasting decrease of PLP, whereas cathodal tDCS of PPC induced a selective short-lasting decrease of nonpainful phantom sensations; stump pain and telescoping were not affected by parietal or by motor tDCS. These findings demonstrate that painful and nonpainful phantom limb sensations are dissociable phenomena. PLP is associated primarily with cortical excitability shifts in the sensorimotor network; increasing excitability in this system by anodal tDCS has an antalgic effect on PLP. Conversely, nonpainful phantom sensations are associated to a hyperexcitation of PPC that can be normalized by cathodal tDCS. This evidence highlights the relationship between the level of excitability of different cortical areas, which underpins maladaptive plasticity following limb amputation and the phenomenology of phantom limb, and it opens up new opportunities for the use of tDCS in the treatment of PLP.     

An Observational Study of the Effect of Levodopa–Carbidopa Intestinal Gel on Activities of Daily Living and Quality of Life in Advanced Parkinson’s Disease Patients

Introduction

Continuous delivery of levodopa–carbidopa intestinal gel (LCIG) by percutaneous endoscopic gastrojejunostomy (PEG-J) in advanced Parkinson’s disease (PD) patients reduces variability in plasma levels, providing better control of motor fluctuations (“on” and “off” states). The MONOTREAT study assessed the effect of LCIG on activities of daily living, motor and non-motor symptoms, and quality of life in advanced PD patients.

Methods

This prospective, observational study included patients with advanced, levodopa-responsive PD with either 2–4 h of “off” time or 2 h of dyskinesia daily. Patients received LCIG via PEG-J for 16 h continuously. Effectiveness was assessed using Unified PD Rating Scale parts II and III, the Non-Motor Symptom Scale, and the PD Questionnaire-8.

Results

The mean (SD) treatment duration was 275 (157) days. Patients experienced significant improvement from baseline in activities of daily living at final visit (p < 0.05) as well as at months 3 and 6 (p < 0.0001). Patients also experienced significant improvements from baseline in quality of life and non-motor symptoms at all time points (p < 0.001 for all). Specifically, patients manifested significant improvements in mean change from baseline at every study visit in five of nine non-motor symptom score domains: sleep/fatigue, mood/cognition, gastrointestinal tract, urinary, and miscellaneous. One-third of patients (32.8%) experienced an adverse event; 21.9% experienced a serious adverse event; 11.1% discontinued because of an adverse event.

Conclusion

This study demonstrated significant and clinically relevant improvements in measures of activities of daily living, quality of life, and a specific subset of non-motor symptoms after treatment with LCIG.

Funding

AbbVie Inc.

     

Minimally invasive endovascular and biliary treatments of children with acute hepatic artery thrombosis following liver transplantation

Hepatic artery thrombosis is a major problem after pediatric liver transplantation. Ischemia caused by hepatic artery thrombosis results in severe biliary and parenchymal damage and is associated with high rates of graft loss and mortality. We present a case-based pictorial essay to illustrate the role of minimally invasive treatment in the prompt management of acute hepatic artery thrombosis, and the associated biliary complications.     

Induction of inflammatory and immune responses by HMGB1–nucleosome complexes: implications for the pathogenesis of SLE

Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1–nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1β, IL-6, IL-10, and tumor necrosis factor (TNF) α and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2–dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1–nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.     

Palliative medicine and decision science: the critical need for a shared agenda to foster informed patient choice in serious illness

Assisting patients and their families in complex decision making is a foundational skill in palliative care; however, palliative care clinicians and scientists have just begun to establish an evidence base for best practice in assisting patients and families in complex decision making. Decision scientists aim to understand and clarify the concepts and techniques of shared decision making (SDM), decision support, and informed patient choice in order to ensure that patient and family perspectives shape their health care experience. Patients with serious illness and their families are faced with myriad complex decisions over the course of illness and as death approaches. If patients lose capacity, then surrogate decision makers are cast into the decision-making role. The fields of palliative care and decision science have grown in parallel. There is much to be gained in advancing the practices of complex decision making in serious illness through increased collaboration. The purpose of this article is to use a case study to highlight the broad range of difficult decisions, issues, and opportunities imposed by a life-limiting illness in order to illustrate how collaboration and a joint research agenda between palliative care and decision science researchers, theorists, and clinicians might guide best practices for patients and their families.