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Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, Mueller S. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol 2016; 8(35): 1547-1556
Corresponding Author of This Article
Sebastian Mueller, MD, PhD, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69120 Heidelberg, Germany. email@example.com
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M
Vanessa Rausch, Teresa Peccerella, Carolin Lackner, Eray Yagmur, Helmut-Karl Seitz, Thomas Longerich, Sebastian Mueller
Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany
Carolin Lackner, Institute for Pathology, Medical University Graz, 8036 Graz, Austria
Eray Yagmur, Laboratory Diagnostics Center, RWTH-University Hospital Aachen, Aachen and Medical Care Center, Dr. Stein and colleagues, 41169 Mönchengladbach, Germany
Thomas Longerich, Institute of Pathology, RWTH-University Hospital Aachen, 52074 Aachen, Germany
ORCID number: $[AuthorORCIDs]
Author contributions: Rausch V and Mueller S contributed to the conception and design of the study, analyzed and interpreted the data and wrote the manuscript; Rausch V, Peccerella T, Lackner C, Yagmur E and Longerich T contributed to the acquisition and analysis of data; Lackner C, Seitz HK and Longerich T critically revised the manuscript and approved the final version.
Supported byThe German Research Foundation (DFG, RA-2677/1-1); and the Dietmar Hopp-Foundation, No. 2301196.
Institutional review board statement: The study was approved by the Ethical Committee of the University of Heidelberg.
Conflict-of-interest statement: The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Data sharing statement: Patients gave informed consent before inclusion in the study; the presented data are anonymized and the risk of identification is very low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sebastian Mueller, MD, PhD, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69120 Heidelberg, Germany. firstname.lastname@example.org
Telephone: +49-6221-483210 Fax: +49-6221-483494
Received: March 22, 2016 Peer-review started: March 23, 2016 First decision: July 4, 2016 Revised: August 22, 2016 Accepted: September 13, 2016 Article in press: September 18, 2016 Published online: December 18, 2016
To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.
Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.
The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.
In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.
Core tip: The role of the PNPLA3 rs738409 variant (CG and GG) on histology and liver stiffness in response to alcohol detoxification was studied in a large monocentric cohort of heavy drinkers with various stages of ALD. About 20% of our patients with alcoholic liver cirrhosis were attributable to PNPLA3 G variants with an OR to develop cirrhosis of 1.295. Our data further show that PNPLA3 GG carriers primarily develop ballooning and not steatosis causing a delayed resolution of liver stiffness after alcohol withdrawal. We suggest that the delayed ballooning-associated stiffness elevation may contribute to fibrosis progression (see also the sinusoidal pressure hypothesis).
Citation: Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, Mueller S. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol 2016; 8(35): 1547-1556
Alcoholic liver disease (ALD) is the most common chronic liver disease in the Western world. ALD encompasses a broad spectrum of disorders ranging from simple steatosis to severe forms of liver injury, including alcoholic steatohepatitis, fibrosis and cirrhosis. Although the majority (80%-90%) of heavy drinkers with an alcohol consumption > 80 g/d develop steatosis, only 35% show signs of inflammation and about 8%-20% progress to cirrhosis. The underlying molecular mechanisms of disease progression, especially why some patients rapidly progress to severe liver disease, are still poorly understood. In addition, it remains unclear whether steatosis necessarily precedes steatohepatitis or is a coinciding bystander. The role of environmental factors that affect disease progression such as drinking habits and comorbidities has been known for many years. However, twin studies, the enhanced sensitivity of female drinkers and the fact that only a minority of patients progress to cirrhosis despite heavy drinking clearly suggest a genetic pre-disposition[4,5].
Recent studies in multiethnic populations with nonalcoholic fatty liver disease (NAFLD) and ALD have demonstrated that the single-nucleotide polymorphism, the rs738409 variant, that encodes for an isoleucine to methionine substitution at position 148 (I148M) in the patatin-like phospholipase-3 (PNPLA3/Adiponutrin) gene is a strong disease modifier by influencing steatosis, liver enzymes and fibrosis progression[6-12]. So far, the function of PNPLA3 and the effect of the amino acid substitution remain controversial. PNPLA3 is closely related to PNPLA2/ATGL, the major hormone-sensitive lipase of adipose tissue, sharing 56% amino acid identity in the patatin-like domain[13,14]. PNPLA3 is expressed in adipocytes, hepatocytes and hepatic stellate cells[15-18]. Despite many efforts, the physiologic role of PNPLA3 and its direct action in the liver is still incompletely understood and it remains unclear whether the I148M substitution in PNPLA3 directly causes steatosis, lipotoxicity, or both.
PNPLA3 GG carriers not only more rapidly progress toward fibrosis but also show elevated liver stiffness (LS). Non-invasive measurement of LS by ultrasound-based elastographic techniques such as transient ela–stography (TE) are increasingly used to screen for liver fibrosis[9,20-25]. However, various conditions have been shown to increase LS in the absence of fibrosis including inflammation and liver damage[26-28], congestion, cholestasis, arterial pressure food intake[32,33] or amyloidosis[34,35]. For these reasons, we here study in detail the impact of PNPLA3 I148M substitution on LS and histology in a large population of heavy drinkers primarily admitted to the hospital for alcohol withdrawal. We further analyze the impact of alcohol withdrawal on LS depending on PNPLA3 status. Our data further suggest that the sustained and drinking-associated LS elevation in PNPLA3 GG carriers is most likely associated with ballooning and seems to contribute to fibrosis progression.
MATERIALS AND METHODS
Caucasian heavy drinkers (n = 521, 148 females/369 males, age range 22-87 years) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0; 95%CI: 179.0-203.3) were enrolled at the Department of Gastroenterology, Salem Medical Center in Heidelberg. Patients presented primarily for alcohol detoxification with a mean duration of chronic alcohol consumption of 19.9 years. Patient’s characteristics are given in Table 1, a more refined PNPLA3 genotype-associated data presentation is shown in Table 2. All patients underwent careful clinical examination, standard laboratory routine (venous blood sampling), abdominal ultrasound and liver stiffness measurement. Inclusion criteria were daily alcohol consumption > 60/80 g/d, age > 18 years, and successful assessment of LS. Other causes of liver diseases (exclusion criteria) were ruled out serologically in all patients by screening for AMA, ANA, HCV and HBV. The study protocol was reviewed and approved by the local Ethics Committee of the University of Heidelberg and all patients gave written informed consent prior to inclusion. Laboratory parameters, TE were performed both at day of admission and release with a mean observation interval of 6.2 ± 3.2 d.
Table 1 Patient characteristics before and after alcohol withdrawal.
Before withdrawal(n = 521)
After withdrawal(n = 370)
50.2 ± 11.3
25.2 ± 4.6
1.0 ± 0.1
Alcohol consumption (g/d)
192.1 ± 139.7
19.9 ± 13.3
Coronary heart disease (%)
Hepatic steatosis (0-3, US)
1.9 ± 0.9
Liver stiffness (kPa)
15.8 ± 21.1
12.6 ± 18.1
101 ± 108
54 ± 48
70 ± 79
52 ± 46
398 ± 577
268 ± 360
109 ± 76
88 ± 55
1.3 ± 2.8
0.9 ± 2.3
5.0 ± 6.0
1.2 ± 3.4
1.2 ± 5.1
22.6 ± 16.6
23.7 ± 12.5
0.7 ± 0.3
0.8 ± 0.2
14.2 ± 2.2
13.8 ± 1.8
209 ± 87
215 ± 82
109.1 ± 36.4
5.6 ± 1.0
195.7 ± 206.6
215.9 ± 58.2
HDL cholesterol (mg/dL)
72.3 ± 36.9
LDL cholesterol (mg/dL)
112.6 ± 45.6
63.6 ± 164.8
60.7 ± 56.3
580.6 ± 650.5
6.1 ± 15.9
7.1 ± 12.5
Data are presented as mean ± SD or in %. BMI: Body mass index; H/W ratio: Hip to waist ratio; RR: Hypertension; F: Fibrosis stage; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl-transpeptidase; AP: Alkaline phosphatase; INR: International normalized ratio (Prothrombin); HDL: High-density lipoprotein; LDL: Low-density lipoprotein; CRP: C-reactive protein; US: Ultrasound.
Table 2 Characteristics of alcoholic liver disease sub-cohorts (n = 521) based on genotype distribution of rs738409 polymorphism.
PNPLA3 CC (n = 204)
PNPLA3 CG (n = 274)
PNPLA3 GG (n = 43)
PNPLA3 CG + GG (n = 317)
49.5 ± 11.0
50.7 ± 11.8
50.1 ± 9.7
50.7 ± 11.5
25.4 ± 4.9
25.1 ± 4.5
25.6 ± 3.9
25.2 ± 4.4
1.0 ± 0.1
1.0 ± 0.1
1.0 ± 0.1
1.0 ± 0.1
Alcohol consumption (g/d)
194.0 ± 136.1
190.8 ± 146.2
181.2 ± 116.1
189.4 ± 142.0
18.3 ± 13.3
20.9 ± 13.1
17.2 ± 14.2
20.4 ± 13.3
Smoker (1 = yes)
0.7 ± 0.4
0.7 ± 0.5
0.6 ± 0.5
0.7 ± 0.5
Diabetes (1 = yes)
0.1 ± 0.3
0.1 ± 0.3
0.0 ± 0.2
0.1 ± 0.3
Coronary heart disease (1 = yes)
0.1 ± 0.2
0.1 ± 0.3
0.0 ± 0.0
0.1 ± 0.3
Hepatic steatosis (0-3, US)
1.8 ± 0.9
2.0 ± 0.8
1.9 ± 0.8
2.0 ± 0.8
Liver stiffness (kPa)
13.1 ± 17.7
17.6 ± 23.0a
17.2 ± 22.2
17.5 ± 22.9a
AST (U/L) before detox
95.2 ± 100.8
102.8 ± 111.4
113.1 ± 116.8
104.0 ± 111.9
AST (U/L) after detox
47.8 ± 32.9
52.6 ± 46.0
82.8 ± 89.5a
56.2 ± 53.5
ALT (U/L) before detox
66.0 ± 59.4
71.9 ± 93.0
76.4 ± 60.4
72.5 ± 89.2
ALT (U/L) after detox
47.5 ± 35.9
52.4 ± 50.9
67.7 ± 55.0a
54.2 ± 51.5
GGT (U/L) before detox
406.3 ± 572.2
365.9 ± 516.1
537.7 ± 869.6
389.6 ± 578.9
GGT (U/L) after detox
254.8 ± 290.9
261.7 ± 347.3
389.7 ± 671.6
276.9 ± 399.6
AP (U/L) before detox
105.5 ± 76.2
111.6 ± 75.8
112.7 ± 72.6
111.8 ± 75.3
AP (U/L) after detox
83.3 ± 45.1
90.5 ± 59.2
97.5 ± 68.4
91.3 ± 60.2
1.2 ± 2.8
1.4 ± 3.0
0.9 ± 1.1
1.3 ± 2.8
4.7 ± 4.7
5.3 ± 7.2
4.5 ± 0.5
5.2 ± 6.7
1.4 ± 5.4
1.0 ± 0.4
0.9 ± 0.2
1.0 ± 0.4
20.6 ± 10.8
24.6 ± 20.2a
20.1 ± 9.9
24.0 ± 19.2a
0.7 ± 0.2
0.7 ± 0.3
0.7 ± 0.2
0.7 ± 0.3
14.2 ± 1.8
14.2 ± 2.5
14.6 ± 2.0
14.2 ± 2.4
216.7 ± 92.7
201.1 ± 80.0a
224.2 ± 91.4
204.5 ± 82.0
112.0 ± 46.2
107.7 ± 28.5
110.7 ± 34.6
108.1 ± 29.3
5.6 ± 1.1
5.6 ± 0.8
5.8 ± 1.3
5.6 ± 0.9
190.6 ± 202.2
192.0 ± 205.8
240.9 ± 230.4
198.7 ± 209.6
219.9 ± 55.0
213.1 ± 61.1
222.9 ± 53.4
214.4 ± 60.1
HDL cholesterol (mg/dL)
73.2 ± 35.9
71.4 ± 37.6
75.6 ± 37.3
71.9 ± 37.5
LDL cholesterol (mg/dL)
113.5 ± 46.3
112.4 ± 45.5
118.0 ± 44.7
113.0 ± 45.3
48.5 ± 45.9
75.9 ± 216.5
45.3 ± 26.0
72.0 ± 202.7
546.1 ± 611.6
599.6 ± 668.3
685.2 ± 708.2
610.8 ± 673.1
4.7 ± 11.1
7.1 ± 18.9
6.0 ± 12.0
7.0 ± 18.1
Data are presented as mean ± SD or in %; significant paired T tests (aP < 0.05) with CC. BMI: Body mass index; H/W ratio: Hip to waist ratio; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl-transpeptidase; AP: Alkaline phosphatase; INR: International normalized ratio (Prothrombin); HDL: High-density lipoprotein; LDL: Low-density lipoprotein; CRP: C-reactive protein; US: Ultrasound; PNPLA3: Adiponutrin.
Liver histology and immunostainings
Eighty patients (15.4%) underwent liver biopsy using the Menghini technique (mean biopsy lengths 15.6 mm). Specimens were fixed in formalin and embedded in paraffin. Two experienced pathologists (TL and CL) blinded to the patient’s data analyzed all liver biopsies independently. For histological analysis, 4 μm sections were dewaxed and stained with hematoxylin and eosin, Chromotrop-Anilinblue and Sirius-Red using standard procedures. Histological semiquantitative scoring of macro- and microvesicular steatosis, lobular inflammation, hepatocellular ballooning, Mallory-Denk bodies and apoptosis as well as fibrosis staging was performed exactly as described by Kleiner et al. In addition, fibrosis was also assessed using the semiquantitative method of Chevallier et al and collagen content was quantified by computer-assisted image analysis of Sirius-Red stained sections (morphometry). The histological diagnosis of steatohepatitis was based on the minimal criteria of steatosis (any degree), lobular inflammation and ballooning.
TE and non-invasive fibrosis assessment in ALD patients
LS was measured by TE (Fibroscan, Echosens SA, Paris, France) using the M or XL probe[40,41]. TE was performed by physicians with at least 12 mo of experience in abdominal ultrasound and transient elastography on the right lobe of the liver in intercostal position according to established protocols. Fibrosis stages were determined using the recently established aspartate transaminase (AST)-adapted cut-off values. In patients with two measurements prior and after alcohol detoxification, the second measurements were used with less pronounced steatohepatitis and transaminase elevation, since such conditions correlate better with histology[9,25]. In addition, liver size, spleen size, ascites formation and semiquantitative liver steatosis (0-3) were assessed by abdominal ultrasound.
Genomic DNA was isolated from EDTA anti-coagulated blood using standard protocols. The PNPLA3 coding SNP I148M was genotyped using tetra-primer ARMS polymerase chain reaction (PCR) technique on the GeneAmp PCR System 2400 (Applied Bioscience) using standard protocol. Primers were designed using Batch Primer 3 software, synthesized by Eurofins MWG Operon (Ebersberg, Germany) and are available upon request. PCR reactions were performed in a total volume of 25 μL, containing approximately 30-50 ng of template DNA, 1 × PCR buffer, 2.5 mmol/L MgCl2, 0.2 mmol/L dNTPs, 2 nmol/L of outer primer and 20 nmol/L inner allele-specific primers and 1U of Taq polymerase (Roche, Penzberg, Germany). Post-PCR allelic discrimination was carried out using horizontal non-denaturing polyacrylamide gel (10%) electrophoresis followed by ethidium bromide staining and visualization on a UV transilluminator. To ensure genotyping quality, we included negative controls and DNA samples with known PNPLA3 genotypes as internal controls.
We used descriptive statistics to compute equally distributed data, including means, standard deviations and frequencies. Not normally distributed data were log transformed before statistical analysis. Comparisons of the genotype distribution of CC, GG and combined CG and GG were performed and the Spearman correlation or χ2 test for non-parametric variables (regression coefficient r, P) was used to determine the associations between laboratory findings, LS, histological scores and the genotypes. To determine whether there are significant differences between the variants (CC, CG, GG or CG combined with GG) we used a two-sample Student’s t-test when the data were normally distributed. Binary logistic regression analysis was calculated to proof possible effects of genotype, gender, age and body mass index (BMI) on the outcome of AST-adapted cut-off values for fibrosis staging. Statistical calculations were performed with SPSS (version 21.0, IBM, SPSS) or SAS (version 9.4, SAS) software and two-sided P values < 0.05 were considered statistically significant. Statistical methods of this study were reviewed by Thomas Bruckner from Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
PNPLA3 rs738409 GG carrier show more cirrhosis
The PNPLA3 rs738409 genotype distribution in our cohort of 521 ALD patients was 39.2%, 52.6% and 8.2% (n = 204, 274 and 43) for CC, CG and GG (Table 2). Notably, fibrosis distribution differed markedly in the non-invasively (n = 521) vs histologically (n = 80) assessed cohorts (Figure 1), histologically characterized patients showed only a small fraction of F0 stages (6%, n = 5). In contrast, the F0 fraction was much higher in the non-invasively assessed cohort by LS (47%, n = 245, Figure 1B). In both approaches, CG + GG carriers had more F4 cirrhosis as compared to CC carriers as shown in Figure 1A (9.3% vs 32.4%) and 1B (16.3% vs 20.0%). CC carriers represented 42.1% of the F0 cohort but 35.5% of the F4 cohort. In other words, about 3.8% more CC carriers had F0 while they were 3.7% less frequent in the non-invasively assessed F4 cohort. Both cohorts did not differ significantly with respect to age and mean drinking duration (approximately 20 years). Linear regression analysis corrected for age, gender and BMI calculated an OR of 1.295 (95%CI: 0.787-2.131) for CG + GG carriers to develop F4 cirrhosis (Table 3). Taken together, our study indicates a PNPLA3-attributable effect on fibrosis stage. Notably and as could be expected, the non-invasively characterized cohort had a much larger proportion of non-fibrotic patients.
Figure 1 Distribution of fibrosis stages using (A) histology (Kleiner fibrosis score F0-4) or (B) non-invasive liver stiffness measurement (aspartate transaminase-adapted cut-off values).aP < 0.05. ns: Not significantly; LS: Liver stiffness.
Table 3 Risk factors associated with F4 cirrhosis.
PNPLA3 G (CG + GG)
BMI: Body mass index; OR: Odds ratio; PNPLA3: Adiponutrin.
PNPLA3 rs738409 GG carriers have no pronounced metabolic phenotype
Since PNPLA3 rs738409 SNP has been primarily identified in NAFLD patients, we next characterized typical features of the NAFLD phenotype. No significant differences were observed between CC, CG and GG carriers with regard to BMI (25.4 vs 25.1 vs 25.6), HbA1c (5.6% vs 5.6% vs 5.8%), and serum fasting glucose concentrations (112 mg/dL vs 108 mg/dL vs 111 mg/dL). This was also the case with regard to coronary heart disease, type II diabetes, smoking habits (assessed by pack years) and arterial hypertension (Table 2 and data not shown). Likewise, no significant differences were observed between levels of high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides (TG) although TG levels were notably higher in GG carriers (Table 2). In summary, in this large cohort of heavy drinkers, GG is associated with advanced fibrosis in the absence of a typical NAFLD-associated metabolic phenotype.
Ballooning/steatohepatitis is the predominant histological feature of PNPLA3 rs738409 GG carrier
To learn more about histological association with the PNPLA3 carrier status, we assessed steatosis, inflammation and fibrosis using the Kleiner and the semiquantitative Chevallier score. Interestingly, GG genotype primarily correlated with steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005), less with steatosis (r = 0.264, P < 0.05) but not significantly with fibrosis (Table 4). In line with this, CC genotype correlated negatively with ballooning (r = -0.221, P < 0.05). These data were mirrored in the direct comparison of the genotypes. More fibrosis and ballooning was present in the CG + GG carriers (Supplemental Table 1). Interestingly, neither a significant association was found with serum markers of liver damage (data not shown), with signs of liver cirrhosis in the ultrasound and with LS. Taken together, liver injury such as ballooning and steatohepatitis are the primary histological features associated with GG genotype in heavy drinkers while fibrosis and steatosis are less pronounced.
Table 4 Spearman rank correlation of PNPLA3 carrier status and liver stiffness with histological parameters.
Liver stiffness primarily correlates with fibrosis and liver damage but not significant with steatosis. In contrast, GG carrier status is tightly associated with liver injury and weakly with steatosis.
aP < 0.05 vs
bP < 0.01. PNPLA3: Adiponutrin.
LS is predominantly associated with fibrosis and ballooning/steatohepatitis but not steatosis
Since previous studies indicated a higher LS in carriers of the PNPLA3 risk allele (CG + GG) in various liver diseases and LS is increasingly used to screen for liver fibrosis, we next carefully analyzed the correlation of LS with histological subscores and the PNPLA3 status (Table 4). As expected, LS showed a very tight and significant association with fibrosis stage (r = 0.828, P < 0.005) but also with ballooning (r = 0.692, P < 0.005) and steatohepatitis (r = 0.391, P < 0.005). Notably, no correlation was observed with steatosis (r = 0.096, ns). In addition, no significant correlation was seen between LS and PNPLA3 genotype. Taken together, in a cohort of heavy drinkers, LS is correlated with fibrosis, liver injury and inflammation but not with steatosis and the PNPLA3 status.
Elevated LS in PNPLA3 rs738409 GG carriers and a delayed resolution after alcohol withdrawal
Mean LS was lowest in CC carriers (13.1 kPa) and significantly higher in CG carriers (17.6 kPa, Figure 2). LS was likewise elevated in GG carriers (17.2 kPa) without reaching statistical significance due to the limited number of patients (8.2%). Interestingly, almost no change was observed in CC carrier after alcohol withdrawal (12.0 kPa, LS2). In contrast, LS significantly decreased in CG carriers to comparable 12.7 kPa after withdrawal from alcohol. Despite a longer observation interval of 6.6 d, LS decreased slower in GG and remained higher (14.5 kPa). This was most likely due to sustained inflammation/ballooning as reflected by elevated AST levels, which were significantly higher after alcohol withdrawal (Figure 2B, Table 2). In summary, GG-associated liver damage results in a reversible, inflammation-associated increase of liver stiffness. In addition, GG carriers show a slower resolution of liver damage and LS after withdrawal from alcohol.
Figure 2 PNPLA3 carrier status and its effect on liver stiffness (A) and aspartate transaminase (B) levels prior and after alcohol detoxification (1 and 2).
Mean observation of detoxification periods in days are indicated for each genotype. aP < 0.05, bP < 0.01. AST: Aspartate transaminase; ALT: Alanine transaminase; LS: Liver stiffness.
We here show in a large monocenter cohort of histologically and non-invasively characterized heavy Caucasian drinkers that the SNP rs738409 in PNPLA3 (CG and GG) is primarily associated with ballooning/steatohepatitis but less with steatosis. Importantly and as seen previously, G carriers (CG + GG) had higher initial LS values as compared to CC carriers. Notably and in some contrast to the genotype analysis, LS was primarily correlated with fibrosis stage, ballooning/steatohepatitis but not at all with steatosis. GG carriers showed a slower resolution of liver damage and LS after withdrawal from alcohol. Since AST levels were significantly elevated in GG carriers after withdrawal from alcohol, we attributed this to delayed resolution of inflammation/ballooning.
Several findings of this study are unexpected and shed new light on the function of PNPLA3 and its link to inflammation and fibrosis development. First of all, we see clear differences of the fibrosis distribution between the biopsy and non-invasively characterized cohorts. While only 6% showed no fibrosis (F0) in the biopsy cohort this number increased drastically to 47% in the non-invasive cohort. These numbers are especially impressive with regard to the high negative predictive values of transient elastography[24,25]. We believe that these findings clearly indicate an often underestimated selection bias of biopsies in ALD study cohorts. Obviously, significantly less patients with no or mild liver disease are asked or motivated to undergo liver biopsy, whereas more severe patients are willing to agree with the invasive procedure. We believe that this observation is a strong argument to enforce well non-invasively characterized ALD cohorts in future studies.
Second, another interesting finding of the non-invasively characterized cohort is the almost symmetric, mirror-like distribution of CC vs G (CG + GG) carriers in the F0 and F4 population over almost 20 years of alcohol consumption. Circa 4% less CC carriers were seen in the cirrhosis group, an equating circa 4% more CC carriers were observed in the F0 group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3-G variants. The odds ratio to develop F4 cirrhosis was 1.3 for our cohort, which corresponds to earlier reports[12,44]. Notably and in line with previous reports, the genotype distribution did not follow the Hardy-Weinberg equilibrium which could point to phenotype (GG)-related increased mortality, e.g., due to complications of cirrhosis such as primary liver cancer (HCC).
Third, the histological findings are intriguing and partly surprising. Up to date, our study presents the most detailed histological analysis with respect to PNPLA3 carrier status and ALD since previous GWAS studies had primarily relied on retrospective samples with laboratory tests such as transaminases and diagnosis of steatosis by ultrasound[10,12]. Our data clearly show that signs of liver injury such as steatohepatitis or ballooning are the major and predominant features of GG carriers. In contrast, other widely discussed findings such as steatosis or fibrosis are less pronounced. Our study suggests that rather ballooning and not steatosis is the key feature of the PNPLA3 GG phenotype in heavy drinkers that later develop ALD. Whether steatosis is either just a consequence of apoptotic liver damage or a bystander needs to be further clarified.
Fourth, special novel insights are seen with the detailed analysis of LS prior and after alcohol withdrawal. It is especially surprising that PNPLA3 status and LS are differentially associated with histology. These data may also serve as explanation for the rather weak effect of the PNPLA3 status on LS and less pronounced results in the past. Thus, LS is highly associated with fibrosis stage (Kleiner and Chevallier) (r = 0.79) and with steatohepatitis/ballooning (r = 0.4-0.7) but not at all with steatosis (r = 0.09). In contrast, the GG status primarily correlates with liver injury (ballooning, steatohepatitis) (r = 0.3-0.5) and weaker with steatosis (r = 0.26). Moreover, a striking feature of the protective CC status is the fast resolution of transaminase levels after alcohol detoxification without notable changes of LS. We can only speculate why CC carriers do not respond with a significant LS decrease after alcohol withdrawal despite an almost normalization of liver transaminases. One explanation could be that only 30% of ALD patients with elevated transaminase levels show a change of LS after alcohol withdrawal. In other words, liver injury as assessed by elevated AST levels not necessarily increases LS in all patients. It rather suggests that ballooning as predominant histological finding of GG carriers may not necessarily cause an increase of transaminase levels. Indeed, ballooning was not significantly associated with elevated AST levels. We therefore believe that GG carriers not only have higher inflammation but also seem to have a slower resolution of liver damage/ballooning. One possible explanation could be that PNPLA3 directly affects pressure-mediated LS elevation according to the recently introduced pressure hypothesis of cirrhosis that also encompasses mechano-signaling. In line with this the co-presence of steatosis in GG carriers could lower LS since steatosis and LS seem not to associate directly (tissue softening of fat).
One of the limitations of our study is the fact that the exact time point of stopping drinking cannot always be determined with absolute correctness nor the adherence to abstaining from alcohol. In addition, the individual response of both laboratory parameters and LS to alcohol withdrawal may also vary considerably. Nevertheless, we strongly feel that the delayed resolution of alcohol-induced inflammation and LS in GG carriers could contribute to fibrosis progression in drinkers who typically show a pulsatile exposure to alcohol and in line with the recently proposed sinusoidal pressure hypothesis. Consequently, GG carriers could have a longer overall exposure to liver inflammation and elevated LS finally resulting in fibrosis progression.
Taken together, liver damage (inflammation/ballooning) with increased LS appears to be the primary event in GG carriers in response to heavy alcohol consumption, which resolves after alcohol withdrawal. Interestingly, GG carriers require a longer period of medical care in the hospital for alcohol detoxification showing advanced liver fibrosis and pointing toward more severe alcohol-related health problems. However, as demonstrated by our non-invasive fibrosis assessment of the whole study population, PNPLA3 carrier status accounts only for circa 20% of alcoholic cirrhosis corresponding to about 4% of our overall study cohort and suggesting additional other, hitherto not recognized pro-fibrogenic factors. On a final note, we would like to emphasize the importance of non-invasive characterization of ALD study cohorts in the light of potential study bias of solely biopsy-based designs.
Polymorphisms of PNPLA3 gene (Adiponutrin) have been identified as important genetic progression factor both of nonalcoholic fatty liver disease and alcoholic liver disease (ALD), the most common liver diseases worldwide. However, PNPLA3 function and its molecular role in liver fibrosis are still unsettled.
Several studies in different populations have confirmed the association of a PNPLA3 polymorphism with chronic liver disorders ranging from steatosis, inflammation to fibrosis progression and even hepatocellular carcinoma. It has also been shown that PNPLA3 I148M elevates liver stiffness, an increasingly used non-invasive parameter to screen for liver cirrhosis.
Innovations and breakthroughs
This is the first study, which investigated in detail the impact of PNPLA3 I148M status, first, on detailed histological subscores in heavy drinkers, and, second, on liver stiffness and other laboratory parameters in response to alcohol withdrawal.
In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of liver stiffness (LS). Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers. Significantly more patients without fibrosis (F0) were seen in the non-invasively characterized cohort as compared to the liver biopsy cohort (47% vs 6%) underlining the potential bias of biopsy-based studies.
ALD is the most common chronic liver disease in the Western world. ALD encompasses a broad spectrum of disorders ranging from simple steatosis to severe forms of liver injury, including alcoholic steatohepatitis, fibrosis and cirrhosis. It has been shown, that the SNP rs738409 in PNPLA3 encoding for an isoleucine to methionine substitution at position 148 (I148M) is a strong liver disease modifier responsible for disease progression.
Rausch et al analyzed the influence of PNPLA3 genotype in heavy drinkers on serum markers and LS during all stages of alcoholic liver disease (steatosis, steatohepatitis and fibrosis) prior and after alcohol detoxification. This is a study of great interest that can help the researchers in evolving in this field.
Manuscript source: Unsolicited manuscript
Specialty type: Gastroenterology and hepatology
Country of origin: Germany
Peer-review report classification
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P- Reviewer: Shih TT, Stasi C, van Erpecum K S- Editor: Gong ZM L- Editor: A E- Editor: Li D
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Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, Hobbs HH. A feed-forward loop amplifies nutritional regulation of PNPLA3.Proc Natl Acad Sci USA. 2010;107:7892-7897.
Lake AC, Sun Y, Li JL, Kim JE, Johnson JW, Li D, Revett T, Shih HH, Liu W, Paulsen JE. Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members.J Lipid Res. 2005;46:2477-2487.
He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, Cohen JC, Hobbs HH. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis.J Biol Chem. 2010;285:6706-6715.
Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, Burza MA, Indiveri C, Ferro Y, Montalcini T. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells.Hum Mol Genet. 2014;23:4077-4085.
Krawczyk M, Grünhage F, Lammert F. Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway.Int J Mol Sci. 2013;14:21153-21166.
Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Lédinghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.Gastroenterology. 2005;128:343-350.
Ganne-Carrié N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, Dhumeaux D, Trinchet JC, Beaugrand M. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases.Hepatology. 2006;44:1511-1517.
Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, Herrmann E. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis.Gastroenterology. 2008;134:960-974.
Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango?Gut. 2010;59:861-866.
Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease.Hepat Med. 2010;2:49-67.
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Sagir A, Erhardt A, Schmitt M, Häussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage.Hepatology. 2008;47:592-595.
Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, Moscarella S, Boddi V, Petrarca A, Laffi G. Acute viral hepatitis increases liver stiffness values measured by transient elastography.Hepatology. 2008;47:380-384.
Dechêne A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP, El Fouly A, Schlattjan M, Saner F, Baba HA, Paul A. Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation.Hepatology. 2010;52:1008-1016.
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Hines CD, Lindstrom MJ, Varma AK, Reeder SB. Effects of postprandial state and mesenteric blood flow on the repeatability of MR elastography in asymptomatic subjects.J Magn Reson Imaging. 2011;33:239-244.
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Southern California always floors us with its environmental variety. When we lived close to Joshua Tree National Park, the town of Idyllwild was just a mere sixty-three miles away. Desert to mountain winter-wonderland in just sixty-three miles (or ~75 minutes in the car)?! Ah-maz-ing! Although it’s not always snowy (duh.) this small town of 2,500 is a great pick any season during the year.
Located in the San Jacinto Mountains and usually a tad less busy than Big Bear, Idyllwild is full of outdoor activities. Whether you’re spending a few days in bustling Palm Springs or visiting J.T, National Park, we encourage you to make a day trip to check it out this peaceful little spot, after all, who can resist an adorable mountain town filled with towering pines, locally owned shops and cute restaurants?
If you’re interested in diving into nature, Idyllwild is loaded with numerous hiking trails that cater to a wide range of ability levels. If you don’t have a ton of time or perhaps you have wee ones we recommend checking out the Erine Maxwell Trail! Although this trail is fairly heavily trafficked, we love it for its simplicity, length, easy difficulty, and beauty. Unlike some of the other hikes in the area, it does NOT require a special permit in addition the the $5 Adventure Pass mentioned below. The gorgeous 5 mile route (2.5 miles each way) winds through the woods and presents with some gorgeous views particularly of Tahquiz Rock). Moreover, with only a slight elevation gain (859 feet) we feel almost anyone interested in hiking can handle it.
To be safe, we would allow 60 – 75minutes each way of hike time or ~2.5hours of daylight to complete the route (although we have done it in as little as 50 minutes each way this is most certainly at a very hustled pace).
Pro Tip: Pack headlamps or your trusty travel flashlight just in case! The day we visited there was fresh snowfall and the parking area was super crowded. The upper parking lot was completely snowed under, so there were only about 9 legal spots just outside the main area. It took us a good bit of time to finally nab a legal parking spot. Not a lot of people were actually on the trail, but quite a few people were there with sleds just to play in the snow. Consequently, we got a bit later start than we were expecting and had to hustle to get back before dark. **Beware, we’ve read in multiple places (including their Facebook page) that they routinely ticket and/or tow vehicles parked illegally.**
Our experience on the trail was obviously dominated by the 18+ inches of snow that dumped on the area the previous week, but overall we found the trail to be easy to moderate in difficulty. It has a pyramidal shaped elevation curve, as you climb from the parking lot up to the highest portion before slowly making your way back down. It’s not overly technical but still provides some amazing views of Tahquiz Rock and the surrounding mountains.
We plan on going back for one of the longer wilderness hikes in the area requiring permits either later in the winter or next spring, so we will make sure to keep this page updated with more info as we get it! There are hundreds of miles of trails in the area, so we will have plenty to keep us busy.
- Hours: Sunrise to Sunset
- Admission: Free
- Parking: Free, however it’s limited at the trailhead, so if you visit during a busy time you may have to stalk someone in order to get one – after all who wants to have a ticket on their windshield after a peaceful hike? Additionally, it’s important to note that you’ll need to obtain an Adventure Pass before parking in order to be 100% legit. You can grab one of these little beauties for $5 at any ranger station. Once you purchase the pass just scratch off the date and then display it from your rearview mirror – easy day.
Mount San Jacinto via Deer Springs Trail
John Muir once wrote that the view from San Jacinto is “the most sublime spectacle to be found anywhere on this Earth.” Well, say no more, we’re going! When we moved to the Southern California Desert in 2019 we spent a good chunk of time exploring with the majority of those trips heading towards Palm Springs. Each drive we would wind around this curve and there staring us in the face would be Mt. San Jac in all its glory. As a result, Dom and I decided – “We gotta climb this thing!” Many folks take the Palm Spring Ariel Tramway and then climb up to the top from there. But Dom and I like a good challenge and thought might as well do the full hike leaving outta Idyllwild splitting it up into two days with the kids in tow!
It was a grand 2-day adventure and we plan on outlining the full trip in later post as honestly this one was one for the books and deserves a page all of its own! If your reading this blog you (probably) have kids and well…we just wanted to give you a friendly reminder to never let anyone ever tell you adventuring stops when you have littles. It simply isn’t true. If you are sitting over there reading this thinking “there is no way my child is going to hike 19+ miles and camp in snow you may or may not be right. However, if you build them up little by little we think you’ll be surprised with how much they are capable of doing. Little people bring challenges, yes, however, they bring so much more than that. Their resilience. Their love for all things great and small as well as their desire to spend time with you make them so of the most awesome travel companions on the planet. Just give them a challenge and watch what they do with it!
Oh, and San Jacinto was one of the most epic hikes we did while in Southern California. Read our full post (coming soon) for all the deets!
Mt. San Jacinto via Deer Springs Trail:
- Hours: Sunrise to Sunset
- Admission: Free
- Parking: Free,
Full disclosure we act as an affiliate for several sites, so clicking through and purchasing products via our links does make us a little money and allows us to continue to put out (hopefully) useful content.

domain: travel


East Anglian Theatre Podcast
Episode 13 - The Peterborough Revellers interview and a review of The Prisoner of Zenda (Quill & Inkling Theatre Co)
July 31, 2022
Ray Tempesta / Alice Hollingdale / Cydney Beagley / Steph Dickenson
An interview with The Peterborough Revellers ahead of their upcoming production of The Little Shop of Horrors, a review of Quill & Inkling's The Prisoner of Zenda, and a look at a few upcoming shows and audition opportunities in the region.


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Despite reports to the contrary, Charlotte FC have not signed Mexico international Andres Guardado, and have no plans to, sources tell MLSsoccer.com.
Charlotte are set to enter MLS in 2022, by which time Guardado will be 35 years old. Currently with Spanish club Real Betis, the midfielder has been heavily linked with a move to MLS at various stages of the last few years.
Charlotte currently have three players on their inaugural roster. They signed Spanish midfielder Sergio Ruiz, Australian midfielder Riley McGree and traded for midfielder Brandt Bronico from Chicago Fire FC.
Ruiz has started 16 matches for Spanish second-tier side Las Palmas, who currently sit in ninth place. He has two goals and two assists. McGree is on loan at Birmingham City in England's Championship, where he's made eight appearances (five starts).
Guardado does have a connection to Charlotte FC, though. Charlotte's director of scouting Thomas Schaling helped bring Guardado to PSV when he was a scout for the Dutch club during the last decade. Guardado spent three seasons with PSV, making more than 100 appearances.
His career began with Atlas in Mexico and he has also played for Deportivo de La Coruña, Valencia and Bayer Leverkusen. Guardado has 162 caps with the Mexican national team.

domain: news


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VietNamNet Bridge – The State Bank of Vietnam (SBV) has released an ultimatum for commercial banks that they must sell all their bad debts by the end of the third quarter of 2015.
Analysts said “not many things have been done” by the Vietnam Asset Management Company (VAMC), which is in charge of buying debt.
However, they said VAMC’s process of buying bad debts from commercial banks would proceed more quickly with many new regulations and the SBV’s strong determination to settle bad debts.
SBV has asked commercial banks to sell at least 75 percent of bad debts by the end of the second quarter, and 100 percent by the end of the third quarter.
The amount of the bad debts banks have to sell will be set by the central bank.
Banks, in fact, have not neglected their task of clearing bad debts. Circular No 36 stipulates that only banks with a bad-debt ratio below 3 percent are eligible to provide credit and buy shares from other credit institutions.
Banks with high bad-debt ratios also face restrictions in opening new branches and providing new loans.
A report shows that VAMC has bought VND137 trillion worth of principal at VND108 trillion paid in special bonds.
It has permission to issue VND80 billion worth of special bonds this year, while planning to buy VND80-100 trillion worth of debts.
Of the VND137 trillion worth of bad debts purchased, only VND5.1 trillion have been settled through compulsory sale and other modes.
Nguyen Duc Kien, deputy chair of the Economics Committee, said that VAMC bought bad debts and then “put it over there”, because it does not know what to do with the debts.
Agribank’s loan worth VND400 billion provided to a three-star hotel developer in Bac Ninh province became a non-performing loan as the developer could not pay the debt.
Agribank sold the hotel to VAMC at VND360 billion, a very high price compared with the market price, estimated at VND200 billion.
However, VAMC cannot sell the hotel at VND200 billion because current laws do not allow it do this.
As such, Kien concluded, the only thing VAMC can do is to keep the hotel for five years before giving it back to the bank.
Dr. Can Van Luc from BIDV said a big gap exists between the price at which VAMC buys debts – equivalent to 80 percent of the debt value, and the price at which VAMC can sell debts – equivalent to 40-50 percent of the debt value.
Đăng ký: VietNam News

domain: finance


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domain: design


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Electro-harmonix launched a new blog series where they highlight ways their pedals are used on guitars to create very un-guitar sounds. For example, the blues harmonica you hear in the track above is actually a guitar. Effectology, Vol. 1: Electric Guitar plays Blues Harmonica
David Pescovitz is Boing Boing's co-editor/managing partner. He's also a research director at Institute for the Future. On Instagram, he's @pesco.


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(See also Causes of Hepatitis Causes of Hepatitis Hepatitis is inflammation of the liver characterized by diffuse or patchy necrosis. Hepatitis may be acute or chronic (usually defined as lasting > 6 months). Most cases of acute viral hepatitis... read more and Overview of Acute Viral Hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more .)
Hepatitis A virus (HAV) is a single-stranded RNA picornavirus. It is the most common cause of acute viral hepatitis and is particularly common among children and young adults.
In some countries, > 75% of adults have been exposed to HAV. In the US in 2018, 12,474 cases were reported, and an estimated 24,900 cases occurred (many cases are not recognized or not reported [ 1 General references Hepatitis A is caused by an enterically transmitted RNA virus that, in older children and adults, causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Young... read more ]). Worldwide, an estimated 1.4 million cases of hepatitis A occur each year (2 General references Hepatitis A is caused by an enterically transmitted RNA virus that, in older children and adults, causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Young... read more ).
HAV spreads primarily by fecal-oral contact and thus may occur in areas of poor hygiene. Waterborne and food-borne epidemics occur, especially in countries that do not have adequate and effective water treatment and sanitation facilities. Eating contaminated raw shellfish is sometimes responsible. Sporadic cases are also common, usually as a result of person-to-person contact.
Fecal shedding of the virus occurs before symptoms develop and usually ceases a few days after symptoms begin; thus, infectivity often has already ceased when hepatitis becomes clinically evident.
HAV has no known chronic carrier state and does not cause chronic hepatitis Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .
Symptoms and Signs of Hepatitis A
In children < 6 years old, 70% of hepatitis A infections are asymptomatic, and in children with symptoms, jaundice is rare. In contrast, most older children and adults have typical manifestations of viral hepatitis Symptoms and Signs Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , including anorexia, malaise, fever, nausea, and vomiting; jaundice occurs in over 70%.
Manifestations typically resolve after about 2 months, but in some patients, symptoms continue or recur for up to 6 months. Some patients have prolonged cholestasis (cholestatic hepatitis) due to hepatitis A; cholestatic hepatitis is characterized by marked jaundice with pruritus, continued fever, weight loss, diarrhea, and malaise.
Recovery from acute hepatitis A is usually complete. Fulminant hepatitis Fulminant Hepatitis Fulminant hepatitis is a rare syndrome of rapid (usually within days or weeks), massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy); it usually occurs after... read more rarely occurs.
Diagnosis of Hepatitis A
In the initial diagnosis of acute hepatitis Initial diagnosis of acute hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more , viral hepatitis should be differentiated from other disorders causing jaundice (see figure Simplified diagnostic approach to possible acute viral hepatitis Simplified diagnostic approach to possible acute viral hepatitis ).
If acute viral hepatitis is suspected, the following tests are done to screen for hepatitis viruses A, B, and C:
IgM antibody to HAV (IgM anti-HAV)
Hepatitis B surface antigen (HBsAg)
IgM antibody to hepatitis B core (IgM anti-HBc)
Antibody to hepatitis C virus (anti-HCV) and hepatitis C RNA (HCV-RNA)
If the IgM anti-HAV test is positive, acute hepatitis A is diagnosed. The IgG antibody to HAV (IgG anti-HAV) test is done (see table Hepatitis A Serology Diagnosis ) to help distinguish acute from prior infection. A positive IgG anti-HAV test suggests prior HAV infection or acquired immunity. There is no further testing for hepatitis A.
HAV is present in serum only during acute infection and cannot be detected by clinically available tests.
IgM antibody typically develops early in the infection and peaks about 1 to 2 weeks after the development of jaundice. It diminishes within several weeks, followed by the development of protective IgG antibody (IgG anti-HAV), which persists usually for life. Thus, IgM antibody is a marker of acute infection, whereas IgG anti-HAV indicates only previous exposure to HAV and immunity to recurrent infection.
Liver tests are needed if not previously done; they include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase.
Other tests should be done to evaluate liver function; they include serum albumin, bilirubin, and prothrombin time/international normalized ratio (PT/INR).
Treatment of Hepatitis A
No treatments attenuate acute viral hepatitis, including hepatitis A. Alcohol should be avoided because it can increase liver damage. Restrictions on diet or activity, including commonly prescribed bed rest, have no scientific basis.
For cholestatic hepatitis, cholestyramine 8 g orally once or twice a day can relieve itching.
Viral hepatitis should be reported to the local or state health department.
Prevention of Hepatitis A
Good personal hygiene helps prevent fecal-oral transmission of hepatitis A. Barrier protection is recommended, but isolation of patients does little to prevent spread of HAV.
Spills and contaminated surfaces in the home of patients can be cleaned with dilute household bleach.
(See also Hepatitis A [HepA] Vaccine Hepatitis A (HepA) Vaccine There are two hepatitis A vaccines; both provide long-term protection against hepatitis A. For more information, see Hepatitis A Advisory Committee on Immunization Practices Vaccine Recommendations... read more ).
The hepatitis A vaccine Hepatitis A (HepA) Vaccine There are two hepatitis A vaccines; both provide long-term protection against hepatitis A. For more information, see Hepatitis A Advisory Committee on Immunization Practices Vaccine Recommendations... read more is recommended for all children beginning at age 1 year, with a 2nd dose 6 to 18 months after the first (see Centers for Disease Control and Prevention [CDC]: Child and Adolescent Immunization Schedule by Age).
Preexposure HAV vaccination (see Adult Immunization Schedule) should be provided for adults with increased risk, including
Diagnostic laboratory workers
Men who have sex with men
People who use injection or noninjection illicit drugs
People with chronic liver disorders (including chronic hepatitis C) because they have an increased risk of developing fulminant hepatitis due to HAV
People who anticipate close contact with an international adoptee during the first 60 days after arrival from a country with high or intermediate HAV endemicity
People who do not have stable housing or who are homeless
Preexposure HAV prophylaxis can be considered for day-care center employees and for military personnel.
Previously, travelers were advised to get the hepatitis A vaccine ≥ 2 weeks before travel; those leaving in < 2 weeks should also be given standard immune globulin. Current evidence suggests immune globulin is necessary only for older travelers and travelers with chronic liver disease or another chronic disorder.
Postexposure prophylaxis should be given to family members and close contacts of patients with hepatitis A.
For healthy, unvaccinated patients aged 1 to 40 years, a single dose of hepatitis A vaccine is given.
For other patients, particularly those > 75 years old, those with chronic liver disease, and immunocompromised patients, standard immune globulin (formerly immune serum globulin) prevents or decreases the severity of hepatitis A. A dose of 0.02 mL/kg IM is generally recommended, but some experts advise 0.06 mL/kg (3 to 5 mL for adults). It can be given up to 2 weeks after exposure, but the earlier, the better.
Hepatitis A virus is the most common cause of acute viral hepatitis; it is spread by the fecal-oral route.
Children < 6 years old may be asymptomatic; older children and adults have anorexia, malaise, and jaundice.
Fulminant hepatitis is rare, and chronic hepatitis, cirrhosis, and cancer do not occur.
Routine vaccination beginning at age 1 is recommended for all.
Vaccinate people at risk (eg, travelers to endemic areas, laboratory workers), and provide postexposure prophylaxis with standard immune globulin or, for some, vaccination.
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Centers for Disease Control and Prevention (CDC): Hepatitis A questions and answers for health professionals: This resource provides an overview of hepatitis A (including diagnosis, statistics, transmission, risk factors, symptoms, and the hepatitis vaccine), as well as information about the use of immune globulin and hepatitis and international travel. Accessed June 8, 2022.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20|
|Locholest , Locholest Light, Prevalite , Questran, Questran Light|
hepatitis a vaccine
|Havrix, Havrix Pediatric , Vaqta|

domain: biology


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Porsche Design and OMA commit to design two towers
Real estate developer Dubai Properties has commissioned the Office for Modern Architecture (OMA) to design two towers in partnership with Porsche Design Studio. The first OMA-designed project to be built in the Middle East, the towers will be built adjacent to one another on the waterfront of Dubai’s Business Bay development.
Real estate developer Dubai Properties has commissioned the Office for Modern Architecture (OMA) to design two towers in partnership with Porsche Design Studio. The first OMA-designed project to be built in the Middle East, the towers will be built adjacent to one another on the waterfront of Dubai’s Business Bay development. The scheme comprises one 85,000m² office block and a 30,000m² residential tower.
OMA partner Rem Koolhaas and senior associate Fernando Donis will be responsible for the design of both buildings, with Porsche Design Studio having a consulting role in the outdoor architecture. Porsche will also be in charge of designing public areas such as lobbies, restaurants and passenger lifts. Residents can request that their apartments be equipped with Porsche Design furniture, lighting and kitchens (see above for examples of a hat stand and bathroom from Porsche Design).
“The idea is that it is Porsche branded – but not only branded, it will contain our design influence throughout,” a spokesperson for the firm confirmed.
The residential tower will be cylindrical in shape, with an interior atrium stretching its full height to allow natural daylight to fill the space. The office tower will have a futuristic glass cube design framed by ‘side wings’ with an external wall of reflective glass that will provide both architectural features and reduce the need for air conditioning. Both towers will include retail and recreational spaces.
Roland Heiler, managing director of the Porsche Design Studio in Zell am See stated: “We are delighted to be able to work on this project with internationally acclaimed partners like Dubai Properties and Rem Koolhaas. The new buildings provide an ideal platform from which we can further expand the presence of our brand in this important region.”
OMA is an international partnership that practices contemporary architecture, urbanism and cultural analysis. It is currently working on a large number of projects in Europe, Asia and North America, including the new head office of Rothschild Bank in London and the 575,000m² China Central Television HQ (pictured top) and Cultural Centre. It has also developed the master plans for projects in Kuwait, Dubai and Ras Al Khaimah. Porsche Design Studio is a subsidiary of the luxury men’s brand Porsche Design. It is one of the most renowned design studios in Europe and works for third parties active in the fields of industrial and product styling. The project is scheduled for completion by the end of 2009.

domain: artistic


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This is not really the kind of photo I usually take, so let me fill you in. This semester, I am taking a web design course for which I have to build an entire new website from scratch. It is fun, though, because I love learning properly how to work with the different codes, from HTML to PHP. And yes, I have dreamed about it at least once. I noticed a flaw in my dream, which seemed like a minor bug (as if a dream normally does make sense), so I wanted to fix the bug by editing the code for my dream. Ooh, what a nerd, I am.
Nevertheless, after a few weeks my website is starting to take off. Every week I am excited to find out about the new assignment, and my teacher seems to be pleased by the result so far. However, I would like to share my project with more people, which is why I am giving you the link. I use the website as a sandbox, where I can test all my newly obtained skills, and be a little bit creative, too. So don’t expect too much from it just yet, and don’t be surprised either when everything changes from time to time.
Perhaps now you understand why I took this photo. I can’t just post a story without a photo to match it. So a couple of weeks ago I went to Kijkduin beach with my dad to take this photo of my ‘artistic interpretaion’ of a sandbox. And as you might now, every photo needs some editing in Photoshop to make it a bit more asthounishing. Since I am not familiar with this kind of photography, I turned to my favorite photoblog by David Anastacio for some inspiration.
If you like this kind of photography, you should check his blog more often. David posts quite regularly, and even was nominated for a Photoblog Award by CoolPhotoblogs.com last year. For me, I love how he turns ordinary situations in extraordinary photographs.


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stand your ground law
The "Stand Your Ground" statute states that “a person who is not engaged in an unlawful activity and who is attacked in any other place where he or she has a right to be has no duty to retreat and has the right to stand his or her ground and meet force with force, including deadly force if he or she reasonably believes it is necessary to do so to prevent death or great bodily harm to himself or herself or another or to prevent the commission of a forcible felony” (Sherman). Many people will say that the “Stand your Ground” law is a great law that has diminished the crime rate, made people feel safer in their neighborhood and has given the people back the power to protect themselves and their loved ones from fatal danger. I would have to
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According to an article published in the South Florida Sun by Nolin, Haughney and Williams “When Lavoie reached into the truck to open the door, Murdock fired. A grand jury, citing Stand Your Ground, absolved him”. In a case like this, one might say that Murdock had a legitimate reason to fear for his life. Lavoie, unknown to Murdock was charging angrily at him; this in most cases would cause a certain amount of fear and would justify defending himself and or his family, but does self-defense always mean killing someone? Why wasn’t there a warning shot or why didn’t he shoot just to incapacitate and not kill, is it because he knew the law would protect him?
Another case that fell under the “Stand Your Ground” law happened In November of 2009. Shane Beil, whose Tavares home business had been burglarized in the past, caught a prowler in his yard early one morning. According to an article published in the South Florida Sun by Nolin, Haughney and Williams “He shot the man, Brett Lee Canada, 23, in the back. He was also cleared under the Stand Your Ground law”. Again, in this case one might feel a certain amount of fear for their lives, but the victim was shot in the back; which in most cases means that he posed no immediate threat to Beil, and the situation could have been handled with a 911 call. That is the problem with this law, there are no specifics governing how the law can and should be used.
The most famous case to date

domain: law


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The Library, which opens on 21 August at noon for women and later at 3pm for men, contains hundreds of books, both Islamic and non-Islamic, for all ages, tastes and attentions including fiction and non-fiction, many of which are unavailable in mainstream libraries.
The library would also have a weekly mother and baby story time sessions for toddlers and pre-schoolers, book clubs, debate clubs, activities and on demand sessions for home schooling families.
MMTQ Manager, Abdussalam Meer said “This unique initiative has been set up to educate and ignite the passion of reading in our young people. It will bring the community together through our storytelling sessions and book clubs”.
For more information visit https://mmtq.org/library/


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The prolonged health and fitness benefits of the right alternatives in diet are as essential as the day-to-day needs of your system. This method for you to incorporate a mixture in your diet plan that can take protective measures, Humana Medicare Advantage Plans 2020 as well as nutritious actions, into mind. The ingredients can even be beneficial if there’s a unique foods piece you need to stay away from. Attempt rather to consume small meals usually. All of these dovetail and interact overall. It can assist in preventing conditions like coronary disease and Humana Medicare Advantage Plans 2020 malignancy due to its fatty acids, iron, phosphorus, https://bit.ly/2PMoDAp and also other nutrition.
Continue reading for some excellent ideas to help you enhance your lifestyle. They can be filled with important nutritional vitamins and will also help your immunity mechanism keep powerful. It is a great idea to get healthy proteins cafes or centered food products prepared in your case when you traveling. Having as much fruits and vegetables as possible will enhance your nutrients. Inadequate nourishment is the best reasons why the body may be developing a difficult time working properly and can bring about serious health issues!
It might be challenging a nutritious meal on the air-port. These food needs to be very low-fat resources for health proteins with sophisticated carbohydrates. Make sure to still eat your healthy proteins at food, just try to eat a lesser quantity and if you are like snacking, grab some carrot sticks.

domain: medical


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What Do Vitamins Do For You?
Having a high intake of vitamins is vital to the health of your body, and there are many benefits to taking vitamins. Vitamins help your body to fight off infections, and they also help your body to convert carbohydrates into energy. They also help to prevent damage to your cells.
Vitamins help the body change carbohydrates into energy
Whether it is for energy or to maintain healthy hair, skin and nails, vitamins are important for human beings. Vitamins are naturally found in many fruits and vegetables and can be obtained in small doses. In addition, some vitamins are toxic if taken incorrectly. There are 13 vitamins required by the human body.
Vitamins can be divided into two main categories: water-soluble and fat-soluble. Water-soluble vitamins are found in the food we eat and are not stored in the body. Fat-soluble vitamins are stored in the liver and muscles. In addition to metabolizing carbohydrates, fat-soluble vitamins also help the body convert fatty acids into energy.
The most important vitamins to the human body are vitamins A, D, E and K. Each vitamin plays a critical role in various cellular processes, from regulating appetite to maintaining blood coagulation. Some vitamins are also needed to help the body break down protein and fat. For example, vitamin E helps the body use vitamin K.
One of the most important vitamins to the human body is vitamin B12. This vitamin helps the body metabolize proteins and carbohydrates. It also plays a role in the synthesis of red blood cells. Vitamin B12 is also needed to promote energy and focus throughout the day. It also helps with mood regulation. It is necessary for the production of cholesterol and hormones.
The best vitamins to take include vitamin E, thiamine, pyridoxine, choline and niacin. These vitamins are essential for normal brain function, skin and hair health, and overall health. The best way to get these vitamins is by eating a healthy balanced diet. Also, avoid drinking alcohol, as it can destroy many B-group vitamins.
Vitamins help prevent damage to cells
Having a good grasp of vitamins and their role in the human body is essential to a healthy lifestyle. Not only do vitamins play a major role in a person’s overall health, they also have the power to ward off common ailments. Despite what many believe, vitamins are not purely synthetic compounds. They are actually organic compounds present in small quantities in a variety of foods. Moreover, they are oftentimes encased in fatty tissue, which makes them more readily absorbable. Having a proper vitamin-rich diet is the best way to ensure that your body gets the nutrients it needs to stay healthy.
Vitamins are important for a variety of reasons, ranging from proper brain function to optimal heart health. For instance, they are necessary for proper cell growth and division. They are also needed to protect the body from infectious agents, such as bacteria and viruses. Vitamins are found in both plant and animal sources. A balanced diet consisting of fruit, vegetables, and nuts is a great place to start. In addition to vitamin C, vitamins A, D, E, and K are also essential to human health. They are stored in the liver, muscles, and fatty tissue. A healthy diet containing these nutrients may also help prevent chronic diseases, such as diabetes.
For the most part, the best vitamins are ingested in small quantities. Moreover, a healthy diet may help avoid heart disease and cancer. A nutrient-rich diet may even improve one’s longevity. This is particularly true for those prone to a degenerative disease, such as Alzheimer’s disease.
Vitamins help fight off infections
Several vitamins are believed to help fight off infections. These include vitamin A, C, D, E, and zinc. These vitamins are naturally found in many foods. They are also available as supplements. They help the body absorb calcium and boost immunity against disease-causing bacteria.
Vitamin C may have a positive effect on a number of infectious agents, including the common cold. It has also been reported to affect maturation of T-lymphocytes. However, the exact mechanism remains unclear.
A number of animal studies have shown that deficiencies in certain nutrients can alter the body’s immune response. It may also increase the risk of infections.
Two Cochrane reviews evaluate vitamin C’s effects on infections. These reviews include a very thorough literature search to identify studies that evaluate the effect of vitamin C on infectious disease. These reviews also do not limit their analysis to particular infections.
The first study was conducted in 1994. It involved elderly people hospitalized for acute bronchitis or pneumonia. The mean plasma vitamin C level was measured at baseline. The researchers concluded that the group that took 0.2 g/day of vitamin C had a lower cold incidence, a shorter cold duration, and a lower respiratory symptom score. The study also found that the effect was significantly different from the placebo group.
The second study was conducted in 2002. The researchers concluded that vitamin C may have a positive effect on herpetic pain. They also reported that it preserved vascular reactivity to acetylcholine in study participants.
Several studies have shown that vitamin C can affect the production of interferon, which helps the body fight off disease. It may also affect the function of phagocytes, which are part of the immune system.
Minerals help your body function
Getting the right amount of minerals is important. This will help your body function properly. Minerals help your body by assisting in the process of creating energy, maintaining blood pressure, regulating hormones, healing wounds and regulating the metabolism of food. Minerals also play a major role in heart and muscle function.
The best way to get minerals is through your diet. However, there are some situations where a diet alone may not provide all the minerals that your body needs. If you have certain health conditions, you may need to consider taking supplements to ensure that your body receives all the nutrients it needs.
Vitamins are a group of nutrients that your body needs to function properly. Vitamins help convert food into energy and repair cellular damage. Vitamins are also important for growth, development and immune function.
There are three types of vitamins. They are vitamin A, vitamin C and vitamin D. Vitamins are water-soluble, so they are easy for your body to absorb.
Vitamins can be broken down by acid. However, some vitamins have antioxidant properties, which help reduce your risk of disease. For example, vitamin C helps produce collagen, which is important for skin, bones and joints.
Calcium is a mineral that helps build strong bones. It also helps to protect against fractures. Calcium is also important in maintaining the proper balance of fluids in the body. Calcium is also important for muscle function.
Potassium is a mineral that helps to send nerve impulses. Potassium also helps to improve muscle function.
Magnesium is a mineral that has many functions in your body. It helps to control blood pressure, stimulate nerve impulses, and aid in muscle contractions. You can find magnesium in almonds, pumpkin seeds, spinach, apricots, prunes, and dairy products.
Micronutrients nourish your body
Using micronutrients is an excellent way to prevent disease and maintain health. They play a key role in every body process. They help your body produce hormones, enzymes, and other substances that are needed for normal growth and development. In addition to supporting the immune system, they also reduce the risk of chronic diseases.
They can be found in food, dietary supplements, and prescriptions. If you are concerned about your intake, talk to your doctor. They can test you for any deficiencies and recommend a nutritional supplement.
The body needs specific amounts of micronutrients to grow and develop. These include calcium, zinc, and selenium. They are also crucial for wound healing and reproduction. They are also important for fighting oxidative damage and protecting the thyroid from disease.
A well-balanced diet is the best way to get these micronutrients. They are found in foods like nuts, seeds, fruits, vegetables, and whole grains. These foods are low in calories and sugar, and high in vitamins and minerals.
Micronutrients also help your body break down carbohydrates, fats, and proteins. This allows your body to use these nutrients in your food for energy. They also help your skin stay healthy and look good. Some micronutrients also act as antioxidants. Antioxidants help fight disease by repairing cells.
Micronutrients help your body to produce hormones, enzymes, and other essential substances. They also play a role in tissue repair and help your muscles move. They are also important for regulating stress responses. They have been found to slow down the aging process.
Most people do not get the recommended amount of these nutrients. Especially in low-income countries, there is a high risk of deficiency. However, most healthy adults can get enough of these micronutrients by eating a balanced diet.

domain: food


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Being out for only just a few days, Tekashi 69’s new album ‘DUMMY BOY’ debuts at the N0.2 spot on the Billboard 200 chart while Travis Scott’s album hits No.1 on the Billboard 200. Billboard reveals that Travis’ Astroworld took returns to the No.1 spot for a third non-consecutive week on Billboard 200.
“The set earned 71,000 equivalent album units in the week ending Nov. 29 (up 60 percent), according to Nielsen Music. Of that sum, 31,000 were in album sales (up 816 percent),” wrote the website. Billboard goes on to explain that, “The Billboard 200 chart ranks the most popular albums of the week in the U.S. based on multi-metric consumption as measured in equivalent album units. Units are comprised of traditional album sales, track equivalent albums (TEA) and streaming equivalent albums (SEA).”
View this post on Instagram
69’s album got leaked online a week ago on Tuesday, November 27 after it was supposed to be released on the 23, but got delayed due to the rapper’s imprisonment.
While in jail, 69 made sure to make his girlfriend feel special on her birthday, by gifting her with a beautiful Rolex that she showed off on social media. “Best birthday EVER!! Thank you baby,” she wrote to twitter. “Your the best even when your not around. Shout out to @jimmyxboi for the drip,” she wrote to Twitter.
— jade (@__ohsoyoujade) November 28, 2018
Tekashi replied to Jade’s Twitter post while in jail, retweeting the picture of her with the new watch and saying, “Real n***a.” Jade has been also posting about how much she misses her boyfriend since he has been locked up. Tekashi 6ix9ine entered a not guilty plea during a hearing on Monday. His trial is expected to start in September of 2019. The rapper, who was charged with six out of the 17 counts issued against the gang will be facing a minimum of 32 years and a maximum of life in prison if convicted.

domain: entertainment


Jun 30, 2015· Kraft pulping process is the most used pulping process in the world. In this process lignin goes into the reactions with the cooking liquor chemicals and split into fragment. In this process lignin goes into the reactions with the cooking liquor chemicals and split into fragment.
Paper Manufacturing Training. These fundamental paper manufacturing elearning courses deliver instruction on safety, maintenance, and the design and operation of papermaking equipment. The subscription has been added to your cart! Click here to view your cart.
products is not common in most manufacturing plants. This paper presents and redefines the concept of project manufacturing and based on a unique and temporary product. The paper examines the scheduling, sequencing, and resource pooling operations required for a .
This research paper centres on one of the key production planning and control functions: sequencing, through an investigation of the impact of the product wheel method on the ordering of products manufactured on a shared manufacturing resource in two process industries. The research paper proceeds as follows.
The manufacturing process is a complex one that can be impacted by many factors: supplies, equipment, factory overhead, the need for special parts, and the people who work at all points in the process. The more variables there are, the greater the possibility of disruption to the smooth operations of a factory.
Oct 13, 2017· Pulp Paper Manufacturing: Inside an Industry in the Process of Reinvention Nestor Rentas October 13, 2017 Uncategorized Leave a Comment As one of the industries most impacted by the digital age, climate change and shifting consumer perspectives, needs and behaviors, pulp and paper could not be at a more critical crossroads.
Step 5 – Core Drying Process. The core is then removed from the winder and dried to solidify the glue, ensuring the core's efficacy as an integral part of your manufacturing process. Responsible Energy. Near our Grunsfeld, Germany plant there is local biomass plant that produces heat and electricity.
Cellular Manufacturing. Cellular manufacturing minimizes the time required to manufacture a single product by moving the product through the entire production process onepiece at a time, at a rate determined by a customer's needs. Cellular manufacturing is in direct contrast to batchandqueue...
The Modern Steel Production Process. Today, steel production makes use of recycled materials as well as traditional raw materials, such as iron ore, coal, and limestone. Two processes, basic oxygen steelmaking (BOS) and electric arc furnaces (EAF), account for virtually all steel production.
The Free Paper Strip Process Timeline is a remarkable design of 6 steps PowerPoint planning presentation. This timeline template is an incredible way to present project planning or Gantt chart. The managers and other business professionals can use this PowerPoint to forecast goals.
Paper production. Further dewatering by mechanical means takes place in the press section where water is taken out of the sheet by pressing between felts. The final drying takes place in the drying section of the machine where the sheet runs against steam heated cylinders to get its final dryness of 9193%.
In essence, a manufacturing process consists of all of the steps required to turn raw materials into usable products people want to buy. Manufacturing has been a major force behind America's growth, making up 12 percent of the economy and adding more than 530,000 jobs since 2010, according to Science Progress, an online journal published by the Center for American Progress.
The Animated Factory Production PowerPoint Template comes with 12 sample slides that provide animations depicting a production process in a factory. With topnotch graphics, animated assembly line layouts and editable objects; this template can be a great resource for making presentations about production processes, factories, blue collar workers, supply chains, etc.
Computer Integrated Manufacturing; Friction Stir Welding; Computeraided manufacturing (CAM) Lubricantfree plastic plain bearing for heavyduty pivoting applications; 3Axis and 5Axis Machining .
Paper Making: Conversion of pulp from stock preparation into a sheet of paper/board using four drinier Machine or Mould machine. Figure MIII gives the details of paper making process. Figure MIII : Paper Making Process STOCK PREPARATION "Beating" and "Refining" are the operation of mechanically treating the pulp fibres.
Smart Factory Applications in Discrete Manufacturing IIC:WHT:IS2::PB: 4 Version Increased Shop Floor Visibility: Greater insight into the production floor enables issues to be identified and addressed before they occur to improve quality control, equipment uptime, and maintenance scheduling.
RealTime, Interactive Work Instructions The following Strategic Initiatives of MESA International are associated with this presentation: Lean Manufacturing Quality Regulatory Compliance Product Lifecycle Management (PLM) ... Manufacturing Process or Mfg Eng, Training Quality Management
Thermal Oxidation. • Usually performed at a temperature between 800 and 1200 ̊̊C, creang a High Temperature Oxide layer • May use either water vapor or molecular oxygen as the oxidant (called either wet or dryoxidation). • Dry Oxidation: slow growth of oxide, high density, high breakdown voltage.
The sequential nature of the manufacturing process dictates that upon completion of each production cycle, each work center must advance a job to the next work center in the manufacturing sequence. The delay of a single job within the sequential manufacturing process disrupts the work flow on the production line and postpones the delivery of every successive airplane by the length of the delay.


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Depeche Mode - Television Archives Live In Cologne album flac
Filmed on location at the Koln Arena, Germany October 1998 0:00 Intro (Painkiller) 0:57 A Question of Time 5:20 It's No Good 9:52 Never Let Me Down Again.
They got Depeche Mode to headline their "Acoustic Christmas" concert. This show was a shorter version of their "Singles Tour" set. Among the highlights are a stripped down rendition of "Enjoy The Silence", and Billy Corgan of The Smashing Pumpkins doing guest guitar and vocal work on "Never Let Me Down Again". The video featured here was recorded "live to tape". All effects, camera changes, and recorded audio was recorded in a raw, "one take" mix. As such, some camera angles, and audio flaws, might pop up from time to time
Construction Time Again. Catching Up With Depeche Mode. Sounds Of The Universe. Live In Berlin Soundtrack. Archives Curator: Daniel Barassi. Go back to the top of this page.
Depeche Mode, news, catalogue, discography, lyrics, world tour information, history, pictures, online music, audio and video. The Best Of Volume 1. The Complete Depeche Mode. Promo other release. Sometimes I Wish I Was Dead. Never Turn Your Back On Mother Earth. Death's Door (Jazz Mix).
Higher LoveSongs of Faith and Devotion Live is Depeche Mode's live album recorded during their worldwide Devotional tour. Title: Songs of Faith Live . Rare Depeche Mode LIVE RECORD COLOGNE GERMANY 1988 - Bootleg. B4 Shake The Disease.
The discography of English electronic music group Depeche Mode consists of 14 studio albums, six live albums, ten compilation albums, 12 box sets, 13 video albums, 55 singles and 70 music videos. The band's music has been released on several labels, including Some Bizzare, Mute Records, Sire Records, Reprise Records, and Columbia Records.
Watch the video for Television Set from Depeche Mode's The 19th Strike for free, and see the artwork, lyrics and similar artists. You can see them running through me baby You can see the lights in their eyes You can see the masses raising me And I'm preaching them more lies I'. ead the full lyrics for Television Set. Discuss these lyrics on MetroLyrics.
From DM Live - The Depeche Mode live encyclopedia for the masses. a Depeche Mode live encyclopedia for the masses. DM Live is an ever-expanding encyclopedia about Depeche Mode to which anyone can contribute.
|2||A Question Of Time|
|3||It's No Good|
|4||Never Let Me Down Again|
|5||Only When I Lose Myself|
|6||Enjoy The Silence|
|9||I Feel You|
NotesTHIS DVD IS NOT FOR SALE!
TRADE BETWEEN FANS ONLY!


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