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25-hydroxycholesterol (25HC), produced by cholesterol 25-hydroxylase (CH25H) in macrophages, has been reported to inhibit the replication of viral pathogens such as severe acute respiratory syndrome coronavirus-2. Also, CH25H expression in macrophages is robustly induced by interferons (IFNs).To better understand the serum level increase of 25HC in coronavirus disease 2019 (COVID-19) and how it relates to the clinical picture.We measured the serum levels of 25HC and five other oxysterols in 17 hospitalized COVID-19 patients.On admission, 25HC and 27-hydroxycholesterol (27HC) serum levels were elevated; however, 7-ketocholesterol (7KC) levels were lower in patients with COVID-19 than in the healthy controls. There was no significant correlation between 25HC serum levels and disease severity markers, such as interferon-gamma (IFN-γ) and interleukin 6. Dexamethasone effectively suppressed cholesterol 25-hydroxylase (CH25H) mRNA expression in RAW 264.7 cells, a murine leukemia macrophage cell line, with or without lipopolysaccharide or IFNs; therefore, it might mitigate the increasing effects of COVID-19 on the serum levels of 25HC.Our results highlighted that 25HC could be used as a unique biomarker in severe COVID-19 and a potential therapeutic candidate for detecting the severity of COVID-19 and other infectious diseases.

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4β-hydroxycholesterol (4βHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6β-epoxycholesterol (5,6βEC), 0.51; cholesterol, 0.70; cholestane-3β,5α,6β-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6βEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4βHC. Substantial FA esterification of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.

For many kinds of cancer, body composition and immunonutritional status have been reported to influence postoperative outcome. We assessed their impact on short- and long-term outcome in patients with colorectal liver metastases who underwent 2-stage liver resections. Short- and long-term outcomes for 47 patients with 2-stage hepatectomies were assessed retrospectively in terms of data obtained before preoperative chemotherapy, before the first hepatectomy, and before the second hepatectomy. Although immunonutritional status and body composition did not affect short-term outcome, high intramuscular fat content before the second hepatectomy was a poor prognostic factor for overall survival (HR, 5.829; 95% CI, 1.611–21.090; p = 0.007) and for recurrence-free survival (HR, 2.787; 95% CI, 1.301–5.973; p = 0.008). Patients with high intramuscular fat before the second hepatectomy also showed shorter intervals from recurrence to treatment failure. Intramuscular fat before the second hepatectomy is an important negative prognosticator in 2-stage liver resection for colorectal liver metastases.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT). The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12). Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups. The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.

During obesity, tissue macrophages increase in number and become proinflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lep

Aims/Introduction This randomized controlled trial aimed to determine whether frequent nutritional education improves the clinical parameters associated with the onset and progression of diabetic kidney disease in type 2 diabetes mellitus patients. Materials and Methods A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit, and the usual intervention group that received nutritional education once a year. The anthropometric parameters, blood pressure, blood chemistry, albuminuria, protein and salt intake, and prescribed medications of 87 patients who completed the 2‐year follow up were analyzed. Results In the intensive intervention group, body mass index and salt intake significantly decreased over the study period. Hemoglobin A1c levels and body fat percentage were significantly lower in the intensive intervention group than in the usual intervention group. At the end of the 2‐year intervention period, the intensive intervention group had significantly lower salt intake (8.1 vs 9.4 g/day) than the usual intervention group. A significant positive correlation was found between salt intake and albuminuria in the overall group and intensive intervention group (r = 0.26, P = 0.02, and r = 0.36, P = 0.02, respectively). The intensive intervention group had a significantly lower insulin use rate than the usual intervention group after the 2‐year intervention period (18% vs 42%). No differences were found in estimated glomerular filtration rate and albuminuria. Conclusion Intensive nutritional education is useful for alleviating the risk factors associated with the onset and progression of diabetic kidney disease.

Objective Both a percutaneous biopsy and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) have been widely performed for liver tumors. However, no studies have compared these two biopsy methods. Method A retrospective study was conducted using medical records for patients who underwent a liver tumor biopsy from 2012 to 2019. The cases were classified into two groups for a comparison: an ultrasound-guided percutaneous biopsy group (percutaneous group) and an EUS-FNA group (EUS group). Results A total of 106 patients (47 in the percutaneous group and 59 in the EUS group) were included. The final diagnosis was malignant in 100 cases and benign in the remaining 6 cases. While the median lesion diameter was 62 mm in the percutaneous group, it was significantly smaller (34 mm) in the EUS group (p

We read with great interest the article titled “ Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus ” (1) published in HepatoBiliary Surgery and Nutrition . Recurrence can follow all treatments, representing a major challenge in treating hepatocellular carcinoma (HCC), as well as the main cause of death following surgery. Presently, guidelines and recommendations for primary HCC are clearly laid out, but recurrent HCC (RHCC) guidelines remain to be established—even though 70% of patients have recurrence within 5 years (2). This highlights the need for practical, stratified guidelines for continued management of these patients.

Type A insulin resistance (IR) syndrome is a severe IR form caused by insulin receptor (INSR) gene defects. Antidiabetic drugs, including high‐dose insulin and insulin‐sensitizing agents, often fail to control associated hyperglycemia. Therapy with recombinant human insulin‐like growth factor 1 can be more effective, but it is expensive. We report a case of type A IR syndrome with an in‐frame INSR heterozygous deletion (ΔLeu999) that was treated with a combination of conventional therapy and ipragliflozin, a sodium–glucose cotransporter 2 inhibitor. Treatment reduced hemoglobin A1c levels (10.0–7.5%) and induced weight loss (54.4–52.0 kg) within 2 months, and the effects were sustained for >3 years. Sodium–glucose cotransporter 2 inhibitors might be useful to normalize blood glucose in type A IR syndrome by reducing bodyweight and ameliorating glucotoxicity., This is the first article to report on the long‐term efficacy of ipragliflozin (a sodium–glucose cotransporter 2 inhibitor) in a patient with insulin receptor mutation. Our findings can be helpful in the development of more effective and affordable treatment strategies for patients with severe insulin resistance syndrome.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell-specific reduction of 3- hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcrm-/m-), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcrm-/m- mice than control Hmgcrfl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcrm-/m- and Hmgcrfl/fl mice with a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell-specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the numbers of ATMs. The ATMs were reduced by decreased recruitment of macrophages due to their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in the adipose tissues. Myeloid cell-specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Summary The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells. Learning points Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development. SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome. Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

A 34-year-old man presented to the emergency department with a chief complaint of epigastric pain. Endoscopic ultrasound detected a 5 mm stone in the common bile duct. After endoscopic sphincterotomy, the black stones and debris were removed with balloon catheter. Abdominal ultrasonography detected no gallbladder stones; hence, the patient was followed up. However, 3 months later, the patient again developed acute cholangitis caused by common bile duct stones and underwent endoscopic stone removal. Cholangiography under balloon occlusion revealed a left hepatic duct diverticulum with an internal defect. Intraductal ultrasonography showed a hyperechoic lesion with acoustic shadow in the diverticulum, suggesting a stone or debris. Therefore, the patient was considered to have had repeated acute cholangitis because of the presence of falling diverticular stones. The patient underwent left hemihepatectomy plus segmentectomy 1 and cholecystectomy. Histopathologically, it was a true diverticulum without internal epithelial atypia. Many debris were seen in the diverticulum. Gallbladder stones were not observed. Eventually, the patient was discharged from the hospital with no postoperative complications and no recurrence of cholangitis after 20 months.

It is known that sarcopenia affects the overall short- and long-term outcomes of patients with gastric cancer (GC); however, the effect of muscle quality on infectious complications after gastrectomy for GC remains unclear. We investigated the associations between the preoperative quantity and quality of skeletal muscle on infectious complications following gastrectomy for GC. The subjects of this retrospective study were 353 GC patients who underwent radical gastrectomy between 2009 and 2018. We examined the relationships between their clinical factors, including skeletal muscle mass index and intramuscular adipose tissue content (IMAC), and infectious complications after gastrectomy. Infectious complications developed in 59 patients (16.7%). The independent risk factors for infectious complications identified by multivariate analysis were male gender (P

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes mellitus. To investigate the role of HMGCR in the development of β cells and glucose homeostasis, we deleted Hmgcr in a β cell-specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in β cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β cell mass and insulin secretion. Ki67 positive cells were reduced in β-KO mice at P9, thus β cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of β cell-associated genes, such as insulin, Pancreatic and duodenal homeobox 1 (Pdx1) and MAF BZIP transcription factor A (Mafa) in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β cells in mice.

Background/Objectives Intraductal papillary mucinous neoplasms (IPMNs) are classified into main duct (MD)-type IPMNs, branch duct (BD)-type IPMNs, and mixed type IPMNs. While MD-type IPMN has a high risk of malignancy and should therefore be considered for resection if the patient is fit, BD-type IPMN needs to be carefully judged for surgical indication. The decision to resect BD-type IPMN is often based on international consensus Fukuoka guidelines 2017, but further investigation is required. In this study, we focused on whether the location of the mural nodule (MN) could be an indicator of malignancy. Methods We enrolled 17 cases who had been diagnosed BD-type IPMNs which were surgically resected from January 2016 to December 2019. These cases were classified into benign and malignant group. Subsequently, a clinicopathological study was conducted based on the localization of MN (MN-central type or MN-peripheral type). Results Although MN was found in 57% (4/11) in the benign group, 88% (7/8) was noted in the malignant group, indicating the presence of MN to be more common in the malignant group. Those with MN consisted of 6 cases of MN-central type and 5 cases of MN-peripheral type. All cases of central type were malignant compared to only one case of the peripheral group being confirmed on histology as cancer. Conclusion BD-IPMN with central mural nodule should be considered high risk for malignancy.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can achieve marked future liver remnant (FLR) hypertrophy but this procedure is associated with a risk of mortality due to liver failure because of an insufficient FLR functional increase, a situation comparable to small-for-size syndrome (SFSS) after living-donor liver transplantation (LDLT).The clinical data, morphologic volume changes, and histopathologic and immunohistochemical findings in hepatocytes and bile ductules were compared between ALPPS (n = 10) and LDLT with a risk for SFSS (n = 12).Although the patient characteristics and short-term outcome differed between the groups, the mean hypertrophy ratios with respect to liver volume for the FLR after performing the first-stage ALPPS procedures resembled those in small-for-size grafts after similar time intervals: 1.702 ± 0.407 in ALPPS vs. 1.948 ± 0.252 in LDLT (P = 0.205). The histologic grades for sinusoidal dilation (P = 0.896), congestion (P = 0.922), vacuolar change (P = 0.964), hepatocanalicular cholestasis (P = 0.969), and ductular reaction (P = 0.728) within the FLR at the second-stage operation during ALPPS or implanted graft were all similar between the groups.The hepatic regenerative process may be similar in ALPPS and LDLT using a small-for-size graft. Reducing the hepatic vascular inflow that may be excessive for the FLR volume during the first stage of ALPPS might enhance the functional recovery since measures with a similar effect appear to lessen the likelihood of SFSS.

Mixed acinar–neuroendocrine carcinoma (MAEC) of the pancreas is a rare entity, and obtaining a preoperative diagnosis is difficult. We report a case of pancreatic MAEC successfully diagnosed with EUS-FNA. The case was a 72-year-old male with upper abdominal pain. Abdominal CT showed an irregular, hypovascular tumor of pancreatic tail. EUS-FNA was performed using a 22G needle. Immunostaining revealed positive results for the acinar marker trypsin and the neuroendocrine markers chromogranin A and synaptophysin. The possibility for MAEC was considered. He underwent distal pancreatectomy and splenectomy. Immunohistochemical examination of the tumor cells showed a wide range of positivity for bcl-10 and trypsin as well as for chromogranin A and synaptophysin, but negative results for CA19-9 and AFP. Considering that ≥ 30% tumors were positive for both acinar and neuroendocrine markers, the patient was diagnosed with MAEC.

Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p

Objective— ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency. Approach and Results— Ldlr -null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1 -null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1 -null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF-α (tumor necrosis factor-α) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein). Conclusions— Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.

Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes. To investigate the role of HMGCR in the development of β-cells and glucose homeostasis, we deleted Hmgcr in a β-cell–specific manner by using the Cre-loxP technique. Mice lacking Hmgcr in β-cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β-cell mass and insulin secretion. Ki67-positive cells were reduced in β-KO mice at P9; thus, β-cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (Ngn3), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of β-cell–associated genes, such as insulin, pancreatic and duodenal homeobox 1 (Pdx1), and MAF BZIP transcription factor A (Mafa) in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β-cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β-cells in mice.

Objective— Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results— We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m− /m − ) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m −/ m − and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m −/ m − macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m −/ m − monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane–associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m −/ m − macrophages. In the setting of Ldlr deficiency, Hmgcr m −/ m − mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m −/ m − macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions— Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.

Aim: Acyl-CoA cholesterol acyltransferase 1 (ACAT1) esterifies free cholesterol to cholesteryl esters (CE), which are subsequently hydrolyzed by neutral cholesterol ester hydrolase 1 (NCEH1). The elimination of ACAT1 in vitro reduces the amounts of CE accumulated in Nceh1-deficient macrophages. The present study aimed at examining whether the loss of ACAT1 attenuates atherosclerosis which is aggravated by the loss of NCEH1 in vivo. Methods: Low density lipoprotein receptor (Ldlr)-deficient mice were transplanted with bone marrow from wild-type mice and mice lacking ACAT1, NCEH1, or both. The four types of mice were fed a high-cholesterol diet and, then, were examined for atherosclerosis. Results: The cross-sectional lesion size of the recipients of Nceh1-deficient bone marrow was 1.6-fold larger than that of the wild-type bone marrow. The lesions of the recipients of Nceh1-deficient bone marrow were enriched with MOMA2-positive macrophages compared with the lesions of the recipients of the wild-type bone marrow. The size and the macrophage content of the lesions of the recipients of bone marrow lacking both ACAT1 and NCEH1 were significantly smaller than the recipients of the Nceh1-deficient bone marrow, indicating that the loss of ACAT1 decreases the excess CE in the Nceh1-deficient lesions. The collagen-rich and/or mucin-rich areas and en face lesion size were enlarged in the recipients of the Acat1−/− bone marrow compared with those of the recipients of the WT bone marrow. Conclusion: The loss of ACAT1 in bone marrow-derived cells attenuates atherosclerosis, which is aggravated by the loss of NCEH1, corroborating the in vitro functions of ACAT1 (formation of CE) and NCEH1 (hydrolysis of CE).

Background The management of severe insulin resistance during pregnancy is challenging because of the increased risk of perinatal complications for both mother and fetus. We describe two consecutive pregnancies in a patient with severe insulin resistance caused by a mutation in the β subunit of the insulin receptor. Case report A non‐obese Japanese woman was diagnosed as having diabetes mellitus during her first pregnancy at age 31 years. She presented at 6 weeks' gestation with a fasting plasma glucose concentration of 15.1 mmol/l and an HbA1c level of 95 mmol/mol (10.8%). Fasting insulin concentration was high at 68.8 μU/ml, suggesting severe insulin resistance. Anti‐insulin and insulin‐receptor antibodies were both negative. Genetic analysis revealed an in‐frame heterozygous deletion mutation (∆Leu999) in the insulin receptor gene. Despite large daily doses (up to 480 units per day) of insulin aspart and isophane, the patient's postprandial plasma glucose level exceeded 11.1 mmol/l. In the patient's second pregnancy, the addition of metformin at a dose of 2250 mg per day achieved tighter glycaemic control, with lower doses of insulin lispro and isophane (up to 174 units/day). Both newborns, who were found to carry the same mutation, were small for gestational age and developed transient hypoglycaemia after birth. Conclusion Adding metformin to the conventional insulin regimen effectively achieved tight glycaemic control with a lower dose of insulin. The mutation of the insulin receptor gene might underlie the intrauterine growth retardation of the newborns. To our knowledge, this is the first report of successful management of diabetes mellitus in a pregnant woman with type A insulin resistance syndrome., What's new This is the first report of successful pregnancy outcomes in a heterozygous carrier of insulin receptor mutation.Adding metformin to conventional insulin regimen enabled the insulin dose to be reduced by > 50% and achieved tight glycaemic control in a severely insulin‐resistant state that developed during pregnancy.Combined therapy can be used as a practical tool for the management of severe insulin resistance such as type A insulin resistance syndrome complicated with pregnancy.

A 68-year-old woman presented with an acute onset of lower abdominal pain. A CT scan of the pelvis showed acute crystal deposition arthritis, and her symptoms markedly reduced with non-steroidal anti-inflammatory drugs. Further, a radiographic evaluation of the right knee joint and CT of the cervical spine revealed calcification; calcium pyrophosphate (CPP) crystals were identified in the synovial fluid of the right knee. This established the diagnosis of CPP crystal deposition disease, while the inflammation of the pubic symphysis was considered as acute crystal deposition arthritis related to calcium pyrophosphate dihydrate crystal deposition. Acute crystal deposition arthritis of the pubic symphysis should be considered in the differential diagnosis of lower abdominal pain.