Prognostic significance of low hepatic fat content in advanced chronic liver disease: MRI-PDFF insights.

INTRODUCTION AND OBJECTIVES: The mechanisms of hepatic fat loss in late-stage metabolic dysfunction-associated fatty liver disease (MASLD) are enigmatic and the prognostic significance of low hepatic fat content (LHF) in chronic liver disease (CLD) is unknown. Proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), is considered the most accurate noninvasive method for quantifying hepatic fat content. This study aimed to address these issues by evaluating PDFF. PATIENTS AND METHODS: This is a single-center, retrospective study involving 762 patients with CLD, measuring liver stiffness (LS) using MR elastography and PDFF using MRI. LHF was defined as a PDFF ≤ 2.7 % and hepatic reserve function was assessed using the albumin-bilirubin (ALBI) score. Multivariate analysis explored associations between variables. RESULTS: LHF was 27 % in the entire cohort, and PDFF was significantly decreased with LS ≥ 5.5 kPa (p < 0.05). On the multivariate analysis, low body mass index and ALBI score were independently associated with LHF (p < 0.05). In advanced CLD (n = 288), ALBI score and PDFF showed a significant negative correlation regardless of etiology (MASLD/non-MASLD: r= -0.613/-0.233), and the prevalence of LHF increased with progression of ALBI grade (p < 0.01 each). In addition, lower PDFF was associated with increased liver-related and all-cause mortality (p < 0.01), and Cox proportional hazards models extracted LHF as an independent prognostic factor, along with ALBI score and hepatocellular carcinoma (p < 0.05 each). CONCLUSIONS: In ACLD, hepatic reserve dysfunction contributed to hepatic fat loss independent of nutritional status, suggesting that LHF may be a poor prognostic factor in all etiologies.

Highly potent anti-human GPVI monoclonal antibodies derived from GPVI knockout mouse immunization.

Recent progress in the understanding of thrombus formation has suggested an important role for glycoprotein (GP) VI in this process. To clarify the exact role in detail, it is necessary to use specific, high affinity inhibitory antibodies. However, possibly due to the conserved structure of GPVI among species, it has been difficult to obtain potent antibodies. In this study, we developed highly potent anti-human GPVI monoclonal antibodies using GPVI knockout mice for immunization. Fab fragments of these antibodies, named OM1 and OM2, potently inhibit collagen-induced platelet aggregation. The IC(50) values for OM1 and OM2 are 0.6+/-0.05 and 1.7+/-0.5 microg/mL, respectively, showing potency greater than, or equal to that of abciximab (1.7+/-0.3 microg/mL), an anti-GPIIb/IIIa antibody. Fab fragments of OM1 and OM2 also potently inhibit collagen-induced ATP release, thromboxane A(2) formation, and platelet adhesion to immobilized collagen under static and flow conditions. Interestingly, platelet aggregation induced with collagen-related peptide was potently inhibited by OM2 but not OM1, indicating that OM1 recognizes an epitope that is different from collagen-related peptide-binding site on GPVI. These results suggest that OM1 and OM2 may be useful tools to understand the role of GPVI in thrombus formation. Furthermore, these antibodies have the potential to be developed as a new class of therapeutic tool.

GPVI-deficient mice lack collagen responses and are protected against experimentally induced pulmonary thromboembolism.

Platelet glycoprotein VI (GPVI) is now considered to be a major player in platelet-collagen adhesive interactions leading to thrombus formation. GPVI blockade, or its depletion, has been shown in mice to result in complete protection against arterial thrombosis, without significant prolongation of bleeding time. GPVI may therefore represent a useful antithrombotic target. In order to reaffirm the role of GPVI in platelet-collagen interactions, we developed GPVI(null) mice by targeted disruption methodology. GPVI(null) mice platelets failed to respond to a high dose of fibrillar collagen, or convulxin, a GPVI agonist, but showed a normal response to other agonists such as ADP, PMA and arachidonic acid. We report, for the first time, that a proportion of GPVI(null) mice is protected against lethal thromboembolism, induced by the infusion of a mixture of collagen and epinephrine. Greater than 55% of GPVI(null) mice survived the challenge, whereas the maximal survival from the other genotypes was 17% (n=18 per genotype). Washed platelets obtained from GPVI(null) mice showed >90% reduction in adhesion to fibrillar collagen under static conditions. Platelet adhesion to collagen under dynamic conditions using a high shear rate (2600 s(-1)) was dramatically reduced using blood from GPVI(null) mice, while platelets from wild-type and heterozygous animals showed a similar amount of adhesion. Animals from each genotype had essentially similar tail bleeding time, suggesting that a complete deficiency of GPVI, at least in mice, does not result in an enhanced bleeding tendency. These observations clearly establish that blockade of GPVI may attenuate platelet-collagen interactions without adversely affecting the bleeding time.

Benign type of central pontine myelinolysis in alcoholism--clinical, neuroradiological and electrophysiological findings.

Nine alcoholic patients with central pontine myelinolysis (CPM),who showed a favorable prognosis, are reported. The majority of them had taken part in binge drinking and had a subsequent consciousness disturbance for 18.1+/-10.9 (mean+/-SD) days. None of the patients had had acute correction of hyponatremia. Truncal ataxia and gait instability were present in most of the patients after recovery from the disturbance of consciousness. Most of them eventually gained independence, and magnetic resonance imaging showed that their pontine lesions tended to shrink. Electrophysiological studies detected prolonged latency between the I and III waves in auditory brainstem responses and between N11 and P13/14 onsets in the somatosensory evoked potentials. These clinical, radiological and electrophysiological findings should be of use in diagnosing CPM.

Low serum amylase levels in drinking alcoholics.

BACKGROUND: We have reported that the serum level of amylase, different from other pancreatic enzymes, increases temporarily after abstinence in alcoholics. To elucidate the mechanism of this phenomenon, pancreatic isoamylase, salivary isoamylase, and amylase in urine were measured together with total serum amylase. METHODS: Total serum amylase, pancreatic isoamylase, and salivary isoamylase values were measured in 38 male patients admitted to the National Alcoholism Center, Kurihama Hospital, for alcoholism after abstinence. In an investigation of amylase secretion, amylase in urine was measured in some patients after abstinence. RESULTS: In the group with abnormally high total serum amylase on admission, levels were found to decrease after abstinence. In patients with pancreatic disorders in this group, abstinence leads to a decrease in total serum amylase, but in patients with no such disorders, total serum amylase increases temporarily due to increases in salivary isoamylase. In the group with normal total serum amylase on admission, levels increased sharply after abstinence, and both pancreatic isoamylase and salivary isoamylase contributed to the gains. In the group with low total serum amylase, a sharp increase of 2-fold or more was noted after abstinence, and a major contributor was pancreatic isoamylase. The ratio of urine amylase to total serum amylase gradually declined, indicating clearly that abstinence led to a decrease in the excretion of amylase in urine. CONCLUSIONS: In cases of heavy alcohol consumption, a decrease in the production or secretion of pancreatic isoamylase and salivary isoamylase while drinking could happen. It was thus suggested that the increase in serum amylase might be due to the fact that this situation is improved by abstinence, plus the fact that excretion of amylase in urine increases during alcohol consumption, and abstinence brings about a decline in such excretion. Measurement of total serum amylase is not appropriate for diagnosing pancreatitis in alcoholic patients or those who consume large quantities of alcohol.

Nuclear localization of alkaline phosphatase in cultured human cancer cells.

The nucleolar localization of alkaline phosphatase (ALPase) was observed by electron microscopic cytochemistry. The culture cells used in this study were normal human cells (fibroblast, WI-38) and human cancer cells (hepatocellular carcinoma, Hep-G2; malignant melanoma, A-375; pancreatic carcinoma, BxPC-3). Cultured cells in almost all strains contained high ALPase activity in the nucleolus, and the localization of ALPase changed during the cell cycle stages. The pattern of ALPase localization during the interphase was divided into three groups: cytoplasmic type, nucleus type, and both types. Moreover, at the mitotic phase, the reaction products were observed on the chromosome. In the cultured malignant melanoma cells, the appearance ratio of ALPase reaction products on the nucleolus (33.9%) showed a higher ratio compared with normal cultured fibroblasts (6.3%). This phenomenon suggests that the high level of the ALPase reaction product may be related to the high level of proliferation of cancer cells.

Alteration of methamphetamine-induced striatal dopamine release in mint-1 knockout mice.

Mint-1, which is also called as X11 or mammalian Lin10, protein has been implicated in the synaptic vesicle exocytosis and the targeting and localization of synaptic membrane proteins. Here, we established mint-1 gene knockout (mint-1 KO) mice and investigated vesicular and transporter-mediated dopamine (DA) release evoked by high K(+) and methamphetamine (METH), respectively. Compared with wild-type control, high K(+)-evoked striatal DA release was attenuated, but not significantly, in the KO mice as measured by microdialysis method. The METH-induced DA release was significantly attenuated in the KO mice. In addition, METH-induced stereotypy was also significantly attenuated in the KO mice. Mint-1 KO mice showed more sensitive and prominent behavioral response to an approaching object as compared with wild-type mice. These results suggest that mint-1 protein is involved in transporter-mediated DA release induced by METH.