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Objective: To explore the differential characteristics of the AMA-M2 autoantibody in patients with primary biliary cirrhosis (PBC) and non-PBC patients.

Methods: Patients with abnormal liver function at the Capital Medical University affiliated to Beijing You-an Hospital were enrolled in this study between January 2011 and December 2013. Serum levels of ANA, AMA and AMA-M2 were detected by indirect fluorescence assay and enzyme-linked immunosorbent assay. The patients' clinical data was obtained for retrospective analysis. Statistical analyses were performed using the SPSS 16.0 software. Enumeration data have been presented as numbers and percentages, and were analyzed using the chi-square test and one-way ANOVA test.

Results: Of the 5315 patients with abnormal liver function, 15.3% (811/5315) were AMA-M2 positive patients; among those 811 patients, 78.4% (636) had PBC, 4.4% (36) had PBC overlapping with autoimmune hepatitis (AIH), 4.4% (36) had drug-induced liver injury, 6.5% (53) had hepatitis B, 3.3% (27) had hepatitis C, 0.6% (5) had hepatitis E, 0.9% (7) had alcoholic liver disease, 0.5% (4) had non-alcoholic fatty liver, 0.8% (6) had primary hepatic carcinoma, and 0.1% (1) had infectious mononucleosis. Serum AMA-M2 level was significantly higher in the PBC patients (vs. other groups, P less than 0.001) with the exception of the patients with PBC/AIH overlap syndrome. Among the 811 patients with AMA-M2 positivity, 88.5% (718) showed AMA positivity and 91.1% (739) showed ANA positivity. Serum alanine transferase (ALT) and aspartate transferase (AST) levels were significantly higher in the drag-induced liver injury patients (527.74+/-684.65 U/L, 490.60+/-716.89 U/L) and the hepatitis E patients (1015.94 ± 165.55 U/L, 665.4 ± 297.14 U/L) than in the PBC patients (96.02 ± 115.56 U/L, 94.82 ± 83.32 U/L) (ALT: F =8.041, P < 0.001, P < 0.001; AST: F =8.066, P < 0.001, P < 0.001). Serum alkaline phosphatase (ALP; 265.16 ± 179.08 U/L) and glutamyl transferase (GGT; 332.02 ± 279.29 U/L) were significantly higher in the PBC patients than in the hepatitis B patients (135.35 ± 123.17 U/L, 140.27 ± 229.24 U/L) and the hepatitis C patients (85.65 ± 27.77 U/L, 92.70 ± 125.72 U/L) (ALP: F=3.911, P =0.01, P=0.001; GGT: F=4.081, P <0.001, P < 0.001). The serum IgM level was significantly higher in the PBC patients (4.60 ± 2.67 g/L) than in the patients with drug-induced liver injury (1.76 ± 1.15 g/L), hepatitis B (2.02 ± 1.41 g/L), hepatitis C (1.48 ± 0.92 g/L), hepatitis E (1.40 ± 0.68 g/L), alcoholic liver disease (1.57 ± 1.07 g/L), non-alcoholic fatty liver (1.05 ± 0.72 g/L), and primary hepatic carcinoma (2.64 ± 2.26 g/L) (F=16.83, P < 0.001, P < 0.001, Probability value < 0.001, Probability value < 0.05, Probability value < 0.01, Probability value < 0.05 respectively).

Conclusion: Although detection of serum AMA-M2 is an important feature of PBC diagnostic testing,there is a high ratio of serum AMA-M2 detected in patients with drug-induced liver injury, hepatitis B, C and E, alcoholic liver disease, non-alcoholic fatty liver,and primary hepatic carcinoma. The AMA-M2 positive non-PBC patients still require close observation to watch for future development of PBC.

The long-term effects of maternal diabetes on preterm infant neurodevelopment are unknown. This study aims to determine if there was an increased likelihood of neurodevelopmental impairment in preterm infants born to mothers with diabetes.

A retrospective cohort study was conducted on preterm infants with neurodevelopmental evaluations at 18–36 months corrected age using the Bayley Scales of Infant and Toddler Development Third edition.

680 former preterm infants were evaluated. There was no difference in cognitive, language, and motor scores. Infants born to diabetic mothers with AMA were significantly different in cognitive (adjusted-β (a-β),−7.24 [95%CI, −11.719 to −2.769]; P = 0.002) and language domains (a-β,−7.783 [95%CI, −13.603 to −1.963]; (P = 0.009).

There was no significant difference in neurodevelopmental outcomes of preterm infants exposed to maternal diabetes. Preterm infants born to mothers with diabetes and AMA demonstrated lower cognitive and language scores at 2 years corrected age.

Hello all! I hope you're well.

I am Matt, the Creative Director for Dreams Central, a social entertainment hub being built in Dreams on PS4 & 5.

Dreams Central is a vision I've had for a long time and for the past 3~ years I've dedicated my life to building a virtual world (with inspirations from PlayStation Home, Ready Player One's Oasis and Snow Crash's Metaverse) that caters to all types of gamers and gives people a virtual space to relax, play games, socialise and more.

Feel free to check out our announcement trailer from earlier this year. Since then, our team has been busy reinventing the project with new graphics and lighting, updated environments and more. Check out a preview of that here.

A promise I made to myself was to make this experience completely free to play with no microtransactions, subscriptions or premium currency. This is for the people with no catch and always will be.

After 3~ years of development, me and my small team have decided to take the crowdfunding route on Kickstarter to help us achieve the complete vision for our resort and theme park. We have so many exciting ideas and not enough hours in the day to see them come to life. With our campaign, if we're successful we'll be able to focus all our time on the game and hopefully expand our small creative team into something more.

Joining me on this AMA will be our community manager, Sam.

With that said, ask us anything!

EDIT: We're gonna wrap things up! Thank you all for joining us!! - Sam & Matt

Hey Jason,

I've got a weird question. I'm young, so I'm pretty much asking you how to behave.

People can have a one-sided mentor relationship, where they found somebody whose knowledge is super valuable to them — in this case, it's you, for me. I learn from what you've written/talked online, and I apply stuff.

In our case, I was fortunate enough to talk to you, which was lovely. I tried to keep my personal-case questions to the min, for the sake of the audience.

But my question is: how do people usually take it from here?

Obviously I'd love to have your advice on tough problems that I encounter, but like... how does such a dynamic work? Is it appropriate if I just shoot questions to people I've met online - do ppl do that after just a podcast meeting? How do I know when it's too much?

My best answer is: I can ask you stuff, and if you don't reply I'll just assume you're busy. And if you really don't wanna hear from me, you'll just tell me 'leave me alone'. But how do people do it? How did you get mentorship from somebody you liked?

Moreso, how can I set the ground for max efficiency? I don't plan to go beyond my boundaries of self-respect, but there are things you can do to optimize. I've heard this thing that went along the lines of: as a kid, you don't want to play to win, all the time, at all costs. You want to make yourself likeable enough so that people want to play with you all the time. This way, you get the most practice on the field.

So that's a mental shift that optimizes for a better system of learning.

Likewise, I've seen with mentors that the #1 worst thing you can do is: take their advice, don't implement any of it, keep asking.

The corollary: where applicable, I try to show people I got mentorship from that I applied those things, just so that they know it wasn't a total of wasted breath from them

So yep, a pretty direct question, but: how do I (or any 'mentee' finding a 'mentor') do this properly? With you, or with anybody else whose knowledge I belive highly applies to my situation. What do I put on the table?

This study addressed the hypothesis that utero-placental dysfunction is an underlying mechanism for susceptibility to FGR and stillbirth in AMA pregnancies. Detailed characterisation studies revealed increased placental weight, but reduced placental efficiency, in pregnancies from women of AMA, together with alterations in placental morphology and function resembling the placental phenotype in FGR and stillborn pregnancies. This phenotype was evident despite apparently normal pregnancy outcomes, indicating adverse effects of maternal ageing on the placenta and potential adaptive responses to achieve a normal birthweight. The abnormal placental phenotype was more marked in women ≥40 years of age, consistent with a higher risk of adverse pregnancy outcomes than women aged <35 years³⁶. To exclude confounding effects in clinical studies, we developed a mouse model of AMA. AMA mice experienced a more severe pregnancy phenotype than in the human pregnancies, with reduced fecundity, increased resorptions and late fetal deaths, and over half of the offspring were classed as FGR (fetal weight <5^th centile). Many similarities were detected in the placental phenotype in the mouse model and human pregnancies, particularly increased placental weight, decreased placental efficiency and altered uteroplacental vascular function, although many of the changes were exaggerated consistent with the more severe fetal outcomes detected. These complementary data from human and murine studies support the hypothesis that maternal ageing is associated with placental dysfunction, which may contribute to the higher rates of stillbirth and FGR in AMA pregnancies.

Morphological differences were apparent in the placentas from women of AMA compared to younger counterparts from gestationally matched, uncomplicated pregnancies, including increased numbers of SNAs and reduced rates of trophoblast proliferation. Both are features of placental dysfunction in pathological pregnancies, including FGR, stillbirth and pre-eclampsia^{37, 38}, but also of post-term pregnancies signifying placental ageing³⁹. Placental ageing is a probable cause of the dramatic increased risk of stillbirth in post term pregnancies (>41 weeks gestation)^{3, 6, 40}. Accelerated placental ageing is a potential explanation for a comparable risk of stillbirth in women ≥40 years at 39 weeks gestation⁴⁰. Further mechanistic studies are required to investigate this hypothesis further.

Reduced placental efficiency, indicated by a lower FW:PW ratio⁴¹, occurs in FGR pregnancies⁴². In women ≥40 years with uncomplicated pregnancies, placental weight was higher than in controls. This was accompanied by changes in placental function – namely elevated amino acid transport and augmented relaxation of CPA and myometrial arteries in response to vasodilators – which together would be proposed to be beneficial for fetal growth and survival. The absence of a parallel increase in birthweight is indicative of either deficiencies in other important aspects of placental function, or an adverse maternal environment that is unfavourable to fetal growth. In the context of this AMA environment, there are placental changes in terms of increased size and altered function. Whether these changes are an adaptation by the placenta in order to maintain appropriate growth of the fetus, or simply a consequence of the altered maternal environment, requires further study. These studies provide supportive evidence for the concept of placental adaptations in human pregnancies, as is well established in murine pregnancies⁴³ (e.g. Igf2, placental specific Igf2 and 11-βHSD2 knock out models), where placental amino acid transport is enhanced to compensate for reduced placental size. These support normal fetal growth and failure of the adaptations results in FGR⁴⁴. Such functional adaptions may be driven by fetal nutrient demand, as in the mouse^{43, 45}, or in response to an adverse environment, for example elevated oxidative stress, as reported in neurones^{46, 47}, or as a consequence of the ageing maternal environment.

The measurement of third trimester placental hormones in maternal circulation has been previously studied to assess placental function and risk of adverse pregnancy outcome^{28, 48}. Lower maternal serum PAPP-A in early gestation is associated with PE, prematurity, FGR and stillbirth^{27, 49}, and third trimester concentrations of hPL and PlGF are decreased in FGR^{28, 29, 50}. Lower levels of placental hormones are presumed to infer reduced placental size and/or function in FGR^{28, 49, 51}. Although PlGF concentrations were not altered, the higher PlGF:SFlt ratio indicates higher free bioavailable PlGF, which is consistent with the increased placental size detected. The absence of alterations in hCG, hPL or progesterone concentrations, and the significantly lower PAPP-A, in AMA pregnancies are thus prominent findings given the higher placental weight and instead imply reduced placental endocrine function.

The human studies were complemented by studies of a mouse model of AMA, which showed similarities in pregnancy outcomes to those reported by large epidemiological studies of human AMA pregnancies, including reduced fecundity⁵², increased early fetal loss⁵³, FGR¹⁰ and increased late stillbirths⁵⁴. These were detected at higher frequency than in human pregnancies, indicating a more extreme model, which is valuable in terms of delineating the mechanisms causing stillbirth with AMA. 40 week old mice were chosen as this best represents the age range of women in the human studies^{34, 55}. Similarities were detected in the placental phenotype in both mouse and human studies, most notably increased placental weight and reduced PW:FW. The increase in placental weight was only apparent in viable pups at E17.5, supporting the hypothesis from the human studies for increased placental growth as an adaptation to promote fetal growth and survival. The significant overlap in FW:PW ratios between the maternal age groups in the human pregnancies is likely reflective of the diversity when studying human pregnancy, emphasising the need for an animal model. The biological significance of a moderate change in placental efficiency in humans (12.2% between controls and mothers ≥40 years) is uncertain; however this is consistent with all women having normal outcomes. The much greater reduction in FW:PW in our mouse model (37.4% in AMA from controls) is likely to reflect the more severe phenotype in the mouse model which presents with high rates of FGR and stillbirth.

Enhanced endothelial-dependent relaxation of uterine arteries was also detected in the AMA mouse model, suggesting that the observations in human pregnancies are not an artefact relating to increased parity and prior irreversible pregnancy-related adaptations in older women⁵⁶. A rat model of AMA found raised systolic blood pressure but reduced uterine artery maximal constriction and no differences in endothelial-dependent vascular relaxation in aged pregnant rats compared to young controls³⁵. Comparisons between these models is limited however as their aged dams were calorie constricted and endothelial-independent relaxation of uterine arteries was not reported³⁵.

A major difference was the reduced amino acid transport detected in AMA mice, in contrast to the enhanced transport in human pregnancies. This is probably attributable to the key difference in the models. Placentas from human studies were selected to only include those with birthweights in the normal range to exclude any overt effects of pathology on the placenta, whilst mice experienced severe adverse fetal outcomes. The reduced transport in mice corresponded to 56% of pups being growth restricted. Potential mechanisms for the altered transport include down-regulation of placental mTOR or insulin/IGF-I signalling, both of which are known modulators of ageing⁵⁷ and underpin the reduced amino acid transport in a baboon model of FGR⁵⁸. More detailed temporal studies of the mouse model are required to confirm the mechanistic features and to unravel potential adaptive responses. Furthermore, repeating these mouse studies at an intermediate maternal age bracket, such as 24–26 weeks, may result in an intermediate phenotype less severe than the one used in this study.

A limitation of the mouse model is the fact that AMA mice were significantly heavier than control mice. Although this was highly variable, the effect on pregnancy outcome could not be separated from those of ageing. Although obesity is associated with increased adverse outcomes, including macrosomia and stillbirth^{59, 60}, it is not associated with reduced litter sizes, severe FGR, or increased placental weight^{59, 60}. Furthermore, mouse models of obesity in pregnancy are generated by providing a high fat, obesogenic diet^{61, 62} which may cause adverse outcomes rather than the increased fat mass per se⁶³. The higher pre-pregnancy maternal weight in our AMA mice is not due to dietary alterations and restricting their calorie intake would add further confounders^{64, 65}. Of note, the pregnancy outcomes for AMA mice with greater maternal weight did not differ from AMA mice without significant age-related maternal weight gain. A further limitation of utilising a mouse model of pregnancy is their polytocous nature, introducing potential confounders, including uterine positioning, litter size and litter-mate competition that do not exist in human pregnancies. However, a carefully chosen animal model can complement human studies providing the limitations are identified and understood.

The mechanisms underpinning the abnormal placental phenotype in AMA pregnancies remain unknown, but may be related to the ageing oocyte accumulating genetic (and epigenetic) damage^{66, 67} (Fig. 7). Interestingly, our AMA mouse model shares striking similarities to a mouse model of IVF used to investigate placental function and development⁶⁸ including reduced fetal viability and weight and increased fetal loss and placental size, paired with reduced expression and activity of nutrient transport systems. Epigenetic modulation of imprinted genes, namely H19 and PHLDA2, governing early embryo development was cited as the underlying mechanism⁶⁸. The effect of AMA on the epigenetic modulation of imprinted genes is currently unknown⁶⁹. Alternatively, the ageing maternal environment may also contribute to placental dysfunction (Fig. 7). Ageing is associated with increased levels of inflammatory and oxidative stress markers⁷⁰, many of which have been associated with poor pregnancy outcome independent of maternal age^{71, 72}. Placental ageing is largely attributed to the placenta being a major source of reactive oxygen species (ROS) which leads to oxidative stress, cellular senescence and loss of tissue function^{73, 74}. In in vitro models, ROS exposure reproduces some of the placental phenotype seen in AMA pregnancies, such as increased SNAs²², altered amino acid transport⁴⁶ and decreased proliferation⁷⁵. A recent study reported increased oxidative stress in the utero-placental bed of aged pregnant mice, and partially improved pregnancy outcome with antioxidant treatment⁷⁶. Further studies are required to determine whether these and other factors in the ageing maternal environment are altered in human pregnancies and are directly related to placental function.

In summary, AMA is associated with multiple aspects of placental dysfunction and altered utero-placental vascular function that are detectable even in pregnancies with apparently normal outcomes. Both human and mouse studies provide evidence for placental and vascular adaptations to support fetal growth, which may be necessary to produce a healthy, adequately grown fetus in an adverse environment. Our human model suggests that placentas from women ≥40 years showed the most severe functional changes and this could guide future studies of AMA. Our mouse model of AMA provides evidence that failure of adaptation leads to severely compromised fetal growth and demise and is a valuable model for delineating the mechanisms causing increased rates of FGR and stillbirth with AMA.

We believe that the evidence presented here is sufficient proof of principal that advancing maternal age affects placental function. The human studies provide evidence of placental dysfunction even in pregnancies that end in apparently normal outcomes, implying underlying and currently unidentified stressors in pregnancy. The mouse model of AMA shows severe placental dysfunction consistent with other studies in FGR and enables analyses of adverse outcomes without the confounders present in human studies. We recognise comparisons between the mouse and human studies should be made cautiously, but emphasise that despite differences in the models, many of the same key markers of placental function are altered. These studies provide the first evidence for a link between advancing maternal age and placental dysfunction and identify important avenues for future study.

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Background and Aim: Antimitochondrial autoantibodies (AMA) are known to be a hallmark of primary biliary cirrhosis, and it has been suggested that AMA play a crucial role in generating biliary changes. Biliary tract lesions are not uncommon in patients with autoimmune hepatitis (AIH) and previous works have demonstrated that AMA are occasionally detectable in sera of patients with AIH. Therefore, the role of AMA as a cause of bile duct lesions in AIH livers should be addressed. The aim of the present study was to determine whether the presence of AMA is associated with clinical features, especially the occurrence of bile duct lesions, in patients with AIH.
Methods: Forty-one patients diagnosed as having AIH according to the revised scoring system of the International Autoimmune Hepatitis Group were enrolled in this study. Clinical data were retrospectively reviewed, and histological findings of the liver were investigated. AMA reactivity was determined by immunoblotting using beef heart mitochondria as antigens.
Results: Although not found in any enrolled patient by conventional indirect immunofluorescence, AMA were detectable in 14 out of 41 patients (34%). Clinical parameters including biochemistry, autoantibody profile, and responses to treatment were similar irrespective of AMA status. Bile duct lesions were noted in 14/14 (100%) and 23/27 (85%) of AMA-positive and -negative patients with AIH, respectively (P = 0.134). There was no statistically significant difference in the grade of inflammation or stage of fibrosis between the two groups.
Conclusion: Antimitochondrial autoantibodies were found to be present in sera of patients with AIH more frequently than expected, even at very low titer. However, clinical features and histological findings of AIH were not influenced by the AMA status.

Antimitochondrial autoantibodies (AMA) are known to be a hallmark of primary biliary cirrhosis (PBC). Serum AMA are detected in more than 90% of patients with PBC, and thus are very valuable for diagnosis of PBC.^[1] Also, based on the high sensitivity and specificity of AMA in PBC, it has been suggested that AMA play a crucial role in generating bile duct lesions that are diagnostic for PBC, such as chronic non-suppurative destructive cholangitis (CNSDC).^[2] It is known that there are some PBC patients with typical pathological and clinical features who are AMA seronegative when measured by indirect immunofluorescence (IIF) as a routine examination. However, we previously demonstrated that serum AMA were detectable even in these patients by immunoblotting using recombinant autoantigens.^[3] In this previous study, 191 PBC sera were tested and the AMA positive rate was 98% (188/191) by immunoblotting, compared to 84% (161/191) by conventional IIF. The fact that AMA are detectable in almost all patients with PBC supports the hypothesis that AMA is a crucial factor in producing histological changes typical in PBC. We also demonstrated that clinical and histological characteristics were quite similar between IIF AMA-positive and negative patients. These results indicate that AMA may be an important factor for generating CNSDC in patients with PBC even if titers are very low; that is, not high enough to be detected by conventional IIF.

Another autoimmune liver disease, autoimmune hepatitis (AIH), is a chronic necroinflammatory liver disease, characterized by elevated serum levels of aminotransferase and immunoglobulins.^[4] Autoimmune reactions against hepatocytes are believed to be pivotal in the immunopathogenesis of AIH, and therefore hepatocyte damage is a main histological feature. However, it has been reported that various changes in the vicinity of biliary tracts are found in livers of patients with AIH.^[5] For example, proliferated, vacuolated, and multilayered bile duct cells as well as lymphocyte infiltration into the duct epithelia are observed,^[6] and designated as hepatitis-associated bile duct lesions (HBL). Czaja et al. also intensively investigated bile duct injury of AIH livers diagnosed using the International Autoimmune Hepatitis Group (IAHG) criteria,^[7,8] and demonstrated that destructive cholangitis and/or ductopenia, considered as hallmarks of histology of PBC, can occur in definite AIH.^[9] However, detection of AMA in sera of patients with AIH is not a rare event. Czaja et al. demonstrated that AMA were detectable in 8 (5%) of 162 patients with AIH using ELISA.^[10] AMA positivity may be higher if immunoblotting using recombinant autoantigens is employed.

Taking all these points into consideration, we hypothesized that AMA might be significant in generating various bile duct lesions in patients with AIH as well. In the present study, we examined the prevalence of AMA using immunoblotting in sera of patients diagnosed with AIH according to the revised IAHG scoring system. Then we compared clinical and histological features of AMA-positive and AMA-negative patients with AIH.

RedSwan CRE is presenting an AMA podcast for the property, Lakehouse in Oakland, California on October 13th, 2021 at 10am CST.

https://us02web.zoom.us/j/83177325772

In recent exciting news for RedSwan CRE, we have started accepting Dogecoin for investment in Lakehouse in Oakland, California. Watch as the RedSwan CRE team discusses the highlights and investment strategies of Lakehouse Oakland, a core fund project in Oakland CA.

Questions about blockchain real estate investments? Lakehouse property? The tokenization process? We're looking forward to answering your questions!

LakeHouse is a fully-entitled 270-unit Opportunity Zone development. The Property is currently a ±0.92 acre unimproved parcel situated at Oakland’s renowned Lake Merritt, the city’s most popular public amenity. The sponsor has approvals to build a 26-story, class-A multifamily tower that will provide a fully amenitized living experience in a premier Oakland submarket that is geographically insulated from potential new competition. Located within walking distance to Lake Merritt BART Station and blocks from Downtown Oakland, LakeHouse benefits from its strategic access to the most innovative companies and highest paying jobs in the world. Median household incomes in Oakland are forecast to grow 20% by 2024 while rental rates are projected to grow 17% during this same time. With its lakefront location and outstanding accessibility to leading employment hubs, LakeHouse provides the rare prospect of investing in a core-quality development with substantial market upside and Opportunity Zone tax benefits.

FID – Flame Ionization Detector
The AVL Flame Ionization Detector (FID) analyzer is designed for measurements of total hydrocarbon (THC) concentrations. It can also optionally measure methane (CH₄) through a converter or via an analytical column (gas chromatography).

CLD – Chemiluminescence Detector
The AVL Chemiluminescence Detector (CLD) analyzer is designed for measurements of nitrogen oxides (NO_X) concentrations in the exhaust gas. It can optionally measure NO and NO_X simultaneously by means of a dual channel setup.

IRD - Infrared Detector
The AVL Infrared Detector (IRD) i60 analyzer is designed for measurements of the concentrations of various infrared active compounds like carbon dioxide (CO₂), carbon monoxide (CO), hexane (C₆H₁₄), nitrous oxide (N₂O) in the exhaust gas.