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Inherited fibrinogen disorders introduce risk for recurrent abortions, sub-chorionic haematoma, placental abruption and postpartum haemorrhage. This is a case report of a successful pregnancy outcome in a 37-year old woman with hypofibrinogenaemia. She was referred to a coagulation test in the first trimester because of history of preeclampsia and HELLP syndrome in previous pregnancy. Hypofibrinogenaemia was diagnosed with fibrinogen level of 0.7 g/L. During the pregnancy she was regularly monitored for fibrinogen levels and multiple cryoprecipitate concentrates were given. She delivered at 39th gestation week, with elective caesarean section under general anaesthesia. There was one episode of postpartum haemorrhage treated with 2 units of red blood cells, repeated infusions of cryoprecipitate to obtain the level of fibrinogen of 2 g/L. She was discharged on the 6th postpartum day in a good condition. In these disorders levels of fibrinogen should be higher than 1 g/L during pregnancy or 2 g/L in case of caesarean section for successful prenatal and peripartal management.

Sepak bola saat ini sudah menjadi sebuah industri yang sangat besar dan melibatkan banyak uang, termasuk besarnya gaji pemain dalam perjanjian kerja, tidak terkecuali di Indonesia. Akan tetapi, seringkali gaji pemain sepak bola di Indonesia tidak terbayarkan. Hal ini terjadi karena kurangnya perlindungan dan pemahaman hukum pemain sepak bola profesional mengenai hak-haknya dalam kontrak kerja. Penelitian ini menggunakan pendekatan yuridis-normatif dan diharapkan memberikan pemahaman mengenai lex sportiva bagi pemain sepakbola di Indonesia. Hasil penelitian menunjukkan bahwa perjanjian kerja pemain sepak bola profesional di Indonesia tunduk pada ketentuan lex sportiva, tetapi perjanjian tersebut juga harus memerhatikan ketentuan hukum kontrak dalam KUHPerdata.AbstractFootball has now become a large industry and involves a lot of money, including the number of the player salaries in an employment agreement, no exception in Indonesia. However, the salaries of football players in Indonesia are unpaid. This happens because the lack of protection and legal understanding of professional football players regarding their rights in employment contracts. This study uses a juridical-normative approach and it expected to provide an understanding of lex sportiva for football players in Indonesia. The conclusion is, even though the employment agreement of football player in Indonesia is subject to the lex sportiva provisions, the agreement should pay attention to the provisions of the contract law in the Civil Code.

it is believed that “ Al-Shadaqah” is giving partially of the wealth to the poor. Al-Asfahani argued that “Al-Shadaqah” is a bride price to the woman. Prophet Muhammad SAW stated that every kindness is Shadaqah. This study aimed to reveal the meaning of Shadaqah based on the word derivation and context which include on semantic studies to disclose the secret meaning and the wisdom in language. It was found that there were five meaning of Shadaqah. In context, shadaqah means in all its forms, zakat, acceptance of repentance, apology and bride price of woman. In term of derivation, it was found that Al Shadaqah has some form of sentences. Here are singular form (Shadaqotun) , Plural form (Shadaqaat), Verb form ( Tashaddaqa ), Present form ( Ashaddaqa), imperative form ( Tashaddaquu) and Noun ( Mutashaddiqun)

Postprandial dyslipidemia is commonly present in people with type 2 diabetes and obesity and is characterized by overproduction of apolipoprotein B48-containing chylomicron particles from the intestine. Peripheral serotonin is emerging as a regulator of energy homeostasis with profound implications for obesity; however, its role in dietary fat absorption and chylomicron production is unknown. Chylomicron production was assessed in Syrian golden hamsters by administering an olive oil gavage and IP poloxamer to inhibit lipoprotein clearance. Administration of serotonin or selective serotonin reuptake inhibitor, fluoxetine, increased postprandial plasma triglyceride (TG) and TG-rich lipoproteins. Conversely, inhibiting serotonin synthesis pharmacologically by p-chlorophenylalanine (PCPA) led to a reduction in both the size and number of TG-rich lipoprotein particles, resulting in lower plasma TG and apolipoprotein B48 levels. The effects of PCPA occurred independently of gastric emptying and vagal afferent signaling. Inhibiting serotonin synthesis by PCPA led to increased TG within the intestinal lumen and elevated levels of TG and cholesterol in the stool when exposed to a high-fat/high-cholesterol diet. These findings imply compromised fat absorption, as evidenced by reduced lipase activity in the duodenum and lower levels of serum bile acids, which are indicative of intestinal bile acids. During the postprandial state, mRNA levels for serotonin receptors (5-HTRs) were upregulated in the proximal intestine. Administration of cisapride, a 5-HT4 receptor agonist, alleviated reductions in postprandial lipemia caused by serotonin synthesis inhibition, indicating that serotonin controls dietary fat absorption and chylomicron secretion via 5-HT4 receptor., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Clustering of the receptors glycoprotein receptor VI (GPVI), C-type lectin-like receptor 2 (CLEC-2), low-affinity immunoglobulin γ Fc region receptor II-a (FcγRIIA), and platelet endothelial aggregation receptor 1 (PEAR1) leads to powerful activation of platelets through phosphorylation of tyrosine in their cytosolic tails and initiation of downstream signaling cascades. GPVI, CLEC-2, and FcγRIIA signal through YxxL motifs that activate Syk. PEAR1 signals through a YxxM motif that activates phosphoinositide 3-kinase. Current ligands for these receptors have an undefined valency and show significant batch variation and, for some, uncertain specificity., Objectives: We have raised nanobodies against each of these receptors and multimerized them to identify the minimum number of epitopes to achieve robust activation of human platelets., Methods: Divalent and trivalent nanobodies were generated using a flexible glycine-serine linker. Tetravalent nanobodies utilize a mouse Fc domain (IgG2a, which does not bind to FcγRIIA) to dimerize the divalent nanobody. Ligand affinity measurements were determined by surface plasmon resonance. Platelet aggregation, adenosine triphosphate secretion, and protein phosphorylation were analyzed using standardized methods., Results: Multimerization of the nanobodies led to a stepwise increase in affinity with divalent and higher-order nanobody oligomers having sub-nanomolar affinity. The trivalent nanobodies to GPVI, CLEC-2, and PEAR1 stimulated powerful and robust platelet aggregation, secretion, and protein phosphorylation at low nanomolar concentrations. A tetravalent nanobody was required to activate FcγRIIA with the concentration-response relationship showing a greater variability and reduced sensitivity compared with the other nanobody-based ligands, despite a sub-nanomolar binding affinity., Conclusion: The multivalent nanobodies represent a series of standardized, potent agonists for platelet glycoprotein receptors. They have applications as research tools and in clinical assays., Competing Interests: Declaration of competing interests S.P.W. and A.S. have a patent for the anti-GPVI nanobody Nb2 (WO2022/136457). All other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1 -/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation., (© 2023. Crown.)

Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes. It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide 2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. In this study, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters after intraduodenal and oral fat administration. GLP-2 treatment in wild-type (WT) mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and protein kinase G (PKG) inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicate an nNOS-PKG-mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production., (© 2022 by the American Diabetes Association.)

Both environmental and genetic factors contribute to relative species abundance and metabolic characteristics of the intestinal microbiota. The intestinal microbiota and accompanying microbial metabolites differ substantially in those who are obese or have other metabolic disorders. Accumulating evidence from germ-free mice and antibiotic-treated animal models suggests that altered intestinal gut microbiota contributes significantly to metabolic disorders involving impaired glucose and lipid metabolism. This review will summarize recent findings on potential mechanisms by which the microbiota affects intestinal lipid and lipoprotein metabolism including microbiota dependent changes in bile acid metabolism which affects bile acid signaling by bile acid receptors FXR and TGR5. Microbiota changes also involve altered short chain fatty acid signaling and influence enteroendocrine cell function including GLP-1/GLP-2-producing L-cells which regulate postprandial lipid metabolism.

Nutrient sensing plays an important role in ensuring that appropriate digestive or hormonal responses are elicited following the ingestion of fuel substrates. Mechanisms of nutrient sensing in the oral cavity have been fairly well characterized and involve lingual taste receptors. These include heterodimers of G protein-coupled receptors (GPCRs) of the taste receptor type 1 (T1R) family for sensing sweet (T1R2-T1R3) and umami (T1R1-T1R3) stimuli, the T2R family for sensing bitter stimuli, and ion channels for conferring sour and salty tastes. In recent years, several studies have revealed the existence of additional nutrient-sensing mechanisms along the gastrointestinal tract. Glucose sensing is achieved by the T1R2-T1R3 heterodimer on enteroendocrine cells, which plays a role in triggering the secretion of incretin hormones for improved glycemic and lipemic control. Protein hydrolysates are detected by Ca 2+ -sensing receptor, the T1R1-T1R3 heterodimer, and G protein-coupled receptor 92/93 (GPR92/93), which leads to the release of the gut-derived satiety factor cholecystokinin. Furthermore, several GPCRs have been implicated in fatty acid sensing: GPR40 and GPR120 respond to medium- and long-chain fatty acids, GPR41 and GPR43 to short-chain fatty acids, and GPR119 to endogenous lipid derivatives. Aside from the recognition of fuel substrates, both the oral cavity and the gastrointestinal tract also possess T2R-mediated mechanisms of recognizing nonnutrients such as environmental contaminants, bacterial toxins, and secondary plant metabolites that evoke a bitter taste. These gastrointestinal sensing mechanisms result in the transmission of neuronal signals to the brain through the release of gastrointestinal hormones that act on vagal and enteric afferents to modulate the physiological response to nutrients, particularly satiety and energy homeostasis. Modulating these orally accessible nutrient-sensing pathways using particular foods, dietary supplements, or pharmaceutical compounds may have therapeutic potential for treating obesity and metabolic diseases.

Background: Agonist stimulation of Group I metabotropic glutamate receptors (mGluRs) initiates their coupling to the heterotrimeric G protein, Gαq/11, resulting in the activation of phospholipase C, the release of Ca(2+) from intracellular stores and the subsequent activation of protein kinase C. However, it is now recognized that mGluR5a also functions as a receptor for cellular prion protein (PrP(C)) and β-amyloid peptide (Aβ42) oligomers to facilitate intracellular signaling via the resulting protein complex. Intracellular mGluR5a signaling is also regulated by its association with a wide variety of intracellular regulation proteins., Results: In the present study, we utilized mass spectroscopy to identify calmodulin kinase IIα (CaMKIIα) as a protein that interacts with the second intracellular loop domain of mGluR5. We show that CaMKIIα interacts with both mGluR1a and mGluR5a in an agonist-independent manner and is co-immunoprecipitated with mGluR5a from hippocampal mouse brain. CaMKIIα positively regulates both mGluR1a and mGluR5a endocytosis, but selectively attenuates mGluR5a but not mGluR1a-stimulated ERK1/2 phosphorylation in a kinase activity-dependent manner. We also find that Aβ42 oligomers stimulate the association of CaMKIIα with mGluR5a and activate ERK1/2 in an mGluR5a-dependent manner. However, Aβ42 oligomer-stimulated ERK1/2 phosphorylation is not regulated by mGluR5a/CaMKIIα interactions suggesting that agonist and Aβ42 oligomers stabilize distinct mGluR5a activation states that are differentially regulated by CaMKIIα. The expression of both mGluR5a and PrP(C) together, but not alone resulted in the agonist-stimulated subcellular distribution of CaMKIIα into cytoplasmic puncta., Conclusions: Taken together these results indicate that CaMKIIα selectively regulates mGluR1a and mGluR5a ERK1/2 signaling. As mGluR5 and CaMKIIα are involved in learning and memory and Aβ and mGluR5 are implicated in Alzheimer's disease, results of these studies could provide insight into potential pharmacological targets for treatment of Alzheimer's disease.