[A case of tuberculous meningitis diagnosed early by direct Loop-Mediated Isothermal Amplification (LAMP) method using centrifuged medium of cerebrospinal fluid culture].

Tuberculous meningitis (TBM) is a central nervous system infection with a high mortality rate and requires early diagnosis and treatment. Identification of Mycobacterium tuberculosis in the cerebrospinal fluid is of primary importance in the diagnosis of TBM, however, conventional methods have some disadvantages: Rapid results tests such as smear and regular PCR method do not have sufficient diagnostic sensitivity; Nested PCR, which is one of the most sensitive tests, is not available in all facilities; Culture tests require a long period of 4-8 weeks for results. Here we report a case of TBM, diagnosed 14 days earlier than culture test by direct Loop-Mediated Isothermal Amplification (LAMP) method using centrifuged medium of cerebrospinal fluid (day 18) culture. The method we used here is simple, widely available, and considered to be useful for early detection of TBM.

Effects of Nutrition Education Program for the Japan Diet on Serum Phospholipid Fatty Acid Compositions in Patients with Dyslipidemia: Re-analysis of Data from a Previous Randomized Controlled Trial.

AIM: We investigated changes in serum phospholipid fatty acid compositions with intake of the Japan Diet (JD) (higher consumption of fish, soybeans, vegetables, seaweed/mushrooms/konjak, and unrefined cereals with reduced consumption of animal fat, meat and poultry with fat, sweets and alcoholic drinks) recommended by the Japan Atherosclerosis Society. METHODS: A randomized parallel controlled clinical trial on JD intake was conducted on Japanese patients with dyslipidemia. Nutrition education, based on the JD or partial JD (PJD) at baseline and at 3 months, was provided and the participants were followed up for 6 months. Fatty acids comprising serum phospholipids were measured in the JD (n=44) and PJD (n=44) groups. RESULTS: Fatty acid intakes of C20:4, C20:5 and C22:6 increased in the JD group as compared with the PJD group. The percentages of serum phospholipid, C22:1 and C20:5 increased, while those of C18:1, C20:3(n-6) and C20:4(n-6) decreased in the JD as compared with the PJD group at 3 months. Changes in the phospholipid concentrations of C20:5, C22:5 and C22:6 reflected those intake volumes. Serum phospholipid C20:5 and C22:6 showed inverse correlations with C18:1, C18:2, and C20:3(n-6) at baseline and the changes at 3 and 6 months. In contrast, no correlation was observed between C20:4(n-6) and those n-3 fatty acids. The ratios of fatty acid concentrations, C16:1/C16:0 and C18:1/C18:0, decreased, but the ratio of C20:4(n-6)/C20:3(n-6) increased in the JD group. CONCLUSION: Nutrition education on the JD changed serum phospholipid fatty acid profiles in favor to prevent against cardiovascular risk factors in patients with dyslipidemia.

HDL Functions-Current Status and Future Perspectives.

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials.

Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin-Cholesterol Acyltransferase Autoantibody.

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Clinically undetected plasmacytoid urothelial carcinoma of the urinary bladder with non-mass-forming metastases in multiple organs: an autopsy case.

This case report outlines a clinically undetected urinary bladder plasmacytoid urothelial carcinoma (PUC) with multiple metastases detected at autopsy. An 89-year-old man presented with edema in the lower limbs. Pleural fluid cytology revealed discohesive carcinomatous cells, although imaging studies failed to identify the primary site of tumor. The patient died of respiratory failure. Autopsy disclosed a prostate tumor and diffusely thickened urinary bladder and rectum without distinct tumorous lesions. Histologically, the tumor consisted of acinar-type prostate adenocarcinoma with no signs of metastasis. Additionally, small, plasmacytoid tumor cells were observed in the urinary bladder/rectum as isolated or small clustering fashions. These metastasized to the lungs, intestine, generalized lymph nodes in a non-mass-forming manner. Combined with immunohistochemical studies, these tumor cells were diagnosed PUC derived from the urinary bladder. Both clinicians and pathologists should recognize PUC as an aggressive histological variant, which can represent a rapid systemic progression without mass-forming lesions.

[A case of recurrent headache and ophthalmoplegia with a contrast-enhanced lesion of the oculomotor nerve in the cavernous region: an atypical phenotype of recurrent painful ophthalmoplegic neuropathy].

The patient was a 14-year-old boy with two previous episodes of self-remitting right ophthalmoplegia with right temporal pain at ages 9 and 12. In 2019, he developed right eyelid ptosis and diplopia 2 days after a pulsating right-sided temporoparietal headache. Recurrent headaches with ophthalmoplegia responded to high-dose steroid therapy, and the clinical features resembled recurrent painful ophthalmoplegic neuropathy (RPON). RPON generally presents with MRI findings of hypertrophy and inflammation at the root of the oculomotor nerve, a vulnerable site of the blood-brain barrier. However, the imaging features in this case were different from those in typical cases of RPON, and oculomotor nerve inflammation was found in the cavernous sinus. The order of onset of headache and oculomotor nerve palsy differed in each recurrence, suggesting that both autoimmune and vascular mechanisms may have been involved in the onset of the disease in our case.

Effects of Dietary Education Program for the Japan Diet on Cholesterol Efflux Capacity: A Randomized Controlled Trial.

AIM: Improving cholesterol efflux capacity (CEC) of high-density lipoprotein (HDL) has been regarded as a novel target for preventing cardiovascular disease. HDL reportedly has antioxidant properties which may contribute to its functions. We investigated changes in CEC with intake of the Japan Diet (JD) recommended by the Japan Atherosclerosis Society and the relationship of these changes to serum antioxidant concentrations. METHODS: A randomized parallel controlled clinical trial on JD intake was performed in Japanese patients with dyslipidemia. Ninety-eight participants were randomly divided into the JD (n=49) or the partial JD (PJD) (n=49) group. Nutrition education, based on each diet at baseline and at 3 months, was provided and the participants were followed up for 6 months. RESULTS: Mean CEC was 1.05 in total and correlated positively with HDL-cholesterol (p＜0.001) at baseline. CEC did not change while oxygen radical absorbance capacity (ORAC) was decreased in both groups (p＜0.001). Although serum total carotenoid increased in both groups, serum α-tocopherol decreased in the JD group as compared to the PJD group (p＜0.05). CEC correlated positively with HDL ORAC at baseline (p=0.021) and with serum total carotenoid at 3 and 6 months (p=0.005, 0.035). Changes in CEC correlated positively with changes in HDL ORAC at 3 months and serum total tocopherol at 3 and 6 months (p＜0.001). CONCLUSION: CEC was not changed by JD education in Japanese patients with dyslipidemia who already had normal CEC at baseline. CEC was suggested to be positively associated with serum α- and γ-tocopherol and HDL ORAC.

Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation.

AIMS: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. METHODS: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using 18fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day, n=16) for 12weeks. 18F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. RESULTS: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%). 18F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of 18F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. CONCLUSIONS: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.

An Atypical Phenotype of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated with Ocular Palsy, IgM-anti Ganglioside Antibody, and Fever-induced Recurrence.

We herein report a case of recurrent multifocal, distal-dominant-sensorimotor neuropathy with ophthalmoplegia, IgM anti-GM1 antibody, and pyrexia-associated relapse. The patient developed sensory disturbance in her limbs after febrile disease at 50 years old. She had experienced several similar episodes and was admitted to the hospital at 56 years old. Based on a pathological study and electrophysiological findings consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), maintenance IVIg therapy was administered and produced partial improvement with no relapse at one-year follow-up. Immunohistochemical studies suggested the presence of IgG (not IgM) anti-myelin antibodies. Chronic neuropathy with ophthalmoplegia and pyrexia-associated relapse may be a unique variant of CIDP.

Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach.

Elevated serum uric acid (SUA)-hyperuricemia-is caused by overproduction of urate or by its decreased renal and/or intestinal excretion. This disease, which is increasing in prevalence worldwide, is associated with both gout and metabolic diseases. Several studies have reported relationships between apolipoprotein E (APOE) haplotypes and SUA levels in humans; however, their results remain inconsistent. This prompted us to investigate the relationship between APOE polymorphisms and SUA levels. Our subjects were 5,272 Japanese men, premenopausal women, and postmenopausal women. Multiple linear regression analyses revealed the ε2 haplotype of APOE to be independently associated with higher SUA in men (N = 1,726) and postmenopausal women (N = 1,753), but not in premenopausal women (N = 1,793). In contrast, the ε4 haplotype was little related to SUA levels in each group. Moreover, to examine the effect of Apoe deficiency on SUA levels, we conducted animal experiments using Apoe knockout mice, which mimics ε2/ε2 carriers. We found that SUA levels in Apoe knockout mice were significantly higher than those in wild-type mice, which is consistent with the SUA-raising effect of the ε2 haplotype observed in our clinico-genetic analyses. Further analyses suggested that renal rather than intestinal underexcretion of urate could be involved in Apoe deficiency-related SUA increase. In conclusion, we successfully demonstrated that the ε2 haplotype, but not the ε4 haplotype, increases SUA levels. These findings will improve our understanding of genetic factors affecting SUA levels.

Current Status of Familial LCAT Deficiency in Japan.

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

Diagnosis and Management of Sitosterolemia 2021.

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.

Effects of Nutrition Education Program for the Japan Diet on Serum LDL-Cholesterol Concentration in Patients with Dyslipidemia: A Randomized Controlled Trial.

AIM: The Japan Diet (JD) recommended by the Japan Atherosclerosis Society based on the traditional Japanese diet is presumably favorable for preventing atherosclerotic cardiovascular diseases, but few high-quality controlled clinical trials have examined its benefits as compared with other diets. We studied effects of nutrition education for JD intake as compared with partial JD (PJD) intake on serum lipids and inflammatory parameters in subjects with dyslipidemia. METHODS: A randomized parallel controlled clinical trial was conducted on outpatients with dyslipidemia. Participants were randomly divided into the JD or the PJD group. Face-to-face nutrition education based on each diet at baseline and at 3 months, as well as monthly counseling by mail during the intervening 3-month period, were provided and participants practiced up to 6 months. Both groups were advised to reduce consumptions of animal fat/ fatty meat/poultry, confections, and alcoholic drinks. Additionally, the JD group participants were recommended to consume more fish, soybean products especially natto, vegetables, and seaweed/mushrooms/konjak, and to switch from refined to unrefined cereals or barley. RESULTS: Mean LDL-cholesterol was 125 +/- 29 mg/dL at baseline, and the JD group ( n=49) showed a greater mean LDL-cholesterol decrease than the PJD group (n=49) [- 8 mg/dL in JD vs 1 mg/dL in PJD, difference, -9 mg/dL (95%CI, -17 to 0) p=0.043)], and triglyceride (p=0.023) and insulin (p=0.033) reductions were larger in the JD group than in the PJD group at 6 months. CONCLUSION: Nutrition education for JD intake was suggested to improve serum lipid and metabolic parameters in patients with dyslipidemia.

High-Density Lipoprotein Cholesterol Efflux Capacity as a Novel Prognostic Surrogate for Coronary Artery Disease.

AIM: We examined the impact of baseline high-density lipoprotein cholesterol efflux capacity (CEC) on major cardiac adverse events (MACE) in patients with coronary artery disease (CAD) during a long-term secondary prevention. METHOD: CEC was measured using a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages in apolipoprotein B-depleted plasma between January 2011 and January 2013. Patients with CAD were divided into 2 groups as a boundary CEC value of 1: 0.19 ≤ CEC ＜1 (impaired CEC group, mean CEC of 0.76±0.16, n=136), and 1 ≤ CEC ≤ 2.08 (enhanced CEC group, 1.20±0.19, n=44). MACE, comprised the incidence of cardiac death, non-fatal myocardial infarction, and any revascularizations (RV) without restenosis approximately 1 year after vascularization, was retrospectively investigated at September 2019. Impact of enhanced CEC on MACE among 22 variables was examined by applying a Cox proportional hazard model. RESULT: The frequency of MACE in impaired CEC group (16.9%, mean observational interval of 2111±888 days) was significantly higher than that in enhanced CEC group (2.3%, 2,252±685, p=0.013), largely driven by the significantly higher RV incidence (14.0 % versus 2.3 %, p=0.032). Enhancement of CEC was the significant predictor of MACE (hazard ratio: 0.11; 95% CI: 0.013-0.879; p=0.038). CONCLUSION: A baseline CEC level of more than 1 in patients with CAD brought favorable long-term clinical outcomes, suggesting that CEC is a useful prognostic and therapeutic surrogate for secondary prevention of CAD.

The fasting 13C-glucose breath test is a more sensitive evaluation method for diagnosing hepatic insulin resistance as a cardiovascular risk factor than HOMA-IR.

BACKGROUND: Although we previously reported the fasting 13C-glucose breath test (FGBT) was useful for the diagnosis of hepatic insulin resistance (IR), there has been no report in an actual clinical setting. We therefore performed the FGBT in patients with heart disease to assess the difference in the diagnostic ability of HIR between the FGBT and HOMA-IR; we also assessed the relationship between the FGBT and known cardiovascular risk factors. METHODS: Two hundred patients (100 with ischemic heart disease [IHD], 50 with non-ischemic heart disease [NIHD], and 50 with non-cardiac lifestyle-related disease [NCD]) participated in this study. The data of 40 healthy volunteers [HV] was obtained in our previous study. We evaluated the 13C excretion rate at 120 min (C120) as the indicator of hepatic IR in the FGBT. RESULTS: The value of C120 in each disease group was significantly lower than in HV, but the HOMA-IR in the IHD and NCD groups was not significantly different from that in HV. The value of C120 significantly correlated with known cardiovascular risk factors. CONCLUSIONS: These results indicated the FGBT is more sensitive than HOMA-IR for evaluating hepatic IR as a cardiovascular risk factor and is likely useful for managing patients to prevent cardiovascular disease.

Reference Intervals of Serum Non-Cholesterol Sterols by Gender in Healthy Japanese Individuals.

AIMS: The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels. METHODS: Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively. RESULTS: The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gender. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99-3.88, 2.14-7.43, and 0.77-3.60 µg/mL in men and 1.03-4.45, 2.19-8.34, and 0.64-2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects. CONCLUSION: These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.

Comparison of Food and Nutrient Intakes between Japanese Dyslipidemic Patients with and without Low-Density Lipoprotein Cholesterol Lowering Drug Therapy: A Cross-Sectional Study.

AIM: We aimed to clarify actual food and nutrient intakes in Japanese patients with dyslipidemia. We also compared food and nutrient intakes between patients with and without low-density lipoprotein cholesterol (LDL-C) lowering drug therapy. METHODS: Food and nutrient intakes were assessed employing 3-day weighted dietary records in this cross-sectional study of 104 Japanese outpatients with dyslipidemia, age 30-65 years, not given dietary counseling. Anthropometric and biochemical parameters were measured after an overnight fast. Food and nutrient intakes were compared between patients with versus without LDL-C lowering drug prescriptions. Stepwise multiple regression analysis was performed to identify relationships between the serum LDL-C concentrations and food intakes. RESULTS: Of the 104 patients, 43.3% were prescribed LDL-C lowering drugs, primarily statins. Of the total patients, 83% had lipid intakes over 25% of total energy consumption (%E), exceeding the recommendation for dyslipidemia by the Japan Atherosclerosis Society. Similarly, 77% had saturated fatty acid intakes over 7%E, and 88% had cholesterol intakes over 200 mg per day. Dietary fiber consumption was low (＜25 g) in 97% of patients. Those taking LDL-C lowering drugs consumed less "meat, poultry and processed meat products" and "cereals", and more "fish", "fruits" and "nuts", than patients not taking these drugs (p＜0.05). Food intakes correlating with LDL-C concentrations independently of drug therapy differed between patients taking versus not taking these medications. CONCLUSION: Our results support the necessity of diet therapy for patients with dyslipidemia regardless of whether LDL-C lowering drugs are prescribed.The clinical trial registration number: UMIN000022955.