Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the alpha2-, beta2-, and beta3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the alpha2A(Lys418Asn)-, beta2(Arg16Gly, Gln27Glu)-, and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of > or =mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in > or =10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.     

Neuroprotection by KATP channels

The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in suppressing the propagation of generalized seizures by its silence. Mice lacking the Kir6.2 subunit of the channels were extremely susceptible to generalized seizures after brief hypoxia. The nigral neuron activity, which is among highest in the brain, was rapidly inactivated during hypoxia by the opening of the post-synaptic ATP-sensitive potassium channels in normal mice, while the neuron activity was enhanced in the mutant mice. During seizure, the cerebral metabolic rate of oxygen increases more than under any other circumstance, leading ultimately to irreversible cell damage. Thus, rapid minimization of energy consumption during metabolic stresses such as hypoxia may be effective protection from the seizure-induced lethal effects. The ATP-sensitive potassium channels in the reticulata neurons may be involved in the protection mechanism against energy-consuming generalized seizure by earlier response to hypoxia than those in other, less active neuron types.     

Bone marrow-restricted involvement of T-cell granular lymphocyte leukemia

A 66-year-old female was referred to our hospital with bone pain and progressive pancytopenia with granular lymphocyte infiltration only in the bone marrow (BM). Flow cytometric and histological analyses revealed that these cells were positive for CD3, TCRalphabeta, granzyme B, and the diagnosis of T-cell granular lymphocyte leukemia (T-GLL) with myelofibrosis was made. These BM granular lymphocytes were greatly ruffled and showed the CD3/CD20 double positive phenotype, which was not detected in the peripheral blood. The patient was treated with a single course of fludarabine followed by a favorable clinical course for 3 months. Many of the BM lymphocytes displayed almost normal appearance after treatment, however, the number of lymphocytes in the BM did not decrease and these were still CD3/CD20 double positive. This is an overlap case of T-GLL and peripheral T-cell lymphoma, unspecified (PTCLu).     

Oral frailty five-item checklist to predict adverse health outcomes in community-dwelling older adults: A Kashiwa cohort study

Aim

To enable easy assessment of oral frailty; that is, an overlapping slight decline in multifaceted oral function, in any setting, we developed the oral frailty five-item checklist (OF-5), and examined its predictive validity for increased risks of physical frailty, physical disability and mortality among community-dwelling older adults.

Methods

This population-based cohort study randomly selected 2044 residents in Kashiwa, Japan, with no long-term care needs. Baseline data were collected in 2012, and follow-up data were collected in 2013, 2014, 2016, 2018 and 2021. The OF-5 includes five measures: fewer teeth, difficulty in chewing, difficulty in swallowing, dry mouth and low articulatory oral motor skills. Physical frailty was defined according to the Cardiovascular Health Study criteria. Physical disability and mortality determined from the long-term care insurance receipt database were followed for 9 years.

Results

Of 2031 eligible participants (mean age 73.1 ± 5.6 years; 51.1% women), 39.3% individuals with ≥2 OF-5 points had significantly increased prevalence and new-onset rate of physical frailty. After adjusting for potential confounders, oral frailty, defined as ≥2 OF-5 points, was associated with increased risks of physical disability (adjusted hazard ratio 1.40; 95% confidence interval 1.14–1.72) and mortality (adjusted hazard ratio 1.44; 95% confidence interval 1.11–1.87). The highest adjusted hazard ratios were observed in older adults with coexisting physical and oral frailty.

Conclusions

The OF-5 showed strong predictive validity for physical frailty, physical disability and mortality in Japanese older adults. This assessment tool can be implemented in various settings and foster comprehensive prevention through interprofessional collaboration. Geriatr Gerontol Int 2023; 23: 651–659 .     

Experimental hypercoagulable state induced by tissue factor expression in monocyte-derived dendritic cells and its modulation by C1 inhibitor

The crosstalk between immune and coagulation systems plays pivotal roles in host defense, which may involve monocyte-derived dendritic cells (moDCs). Our objectives were to elucidate the role of moDCs in coagulation under inflammatory conditions and the involvement of the complement system. We assessed the effects of lipopolysaccharide (LPS)-stimulated moDCs on coagulation using whole blood thromboelastometry in the presence of complement inhibitors. The sum of clotting time and clot formation time (CT plus CFT) in whole blood thromboelastometry was significantly more reduced in the presence of moDCs than in the absence of monocytes or moDCs and in the presence of monocytes, indicating a more potent coagulability of moDCs. The mRNA expression of coagulation-related proteins in moDCs was analyzed by quantitative PCR, which showed an increase only in the mRNA levels of tissue factor (TF). TF protein expression was assessed by western blot analysis and an activity assay, revealing higher TF expression in moDCs than that in monocytes. The in vitro moDC-associated hypercoagulable state was suppressed by a TF-neutralizing antibody, whereas LPS enhanced the in vitro hypercoagulation further. C1 inhibitor suppressed the in vitro LPS-enhanced whole blood hypercoagulability in the presence of moDCs and the increased TF expression in moDCs. These results suggest a significant role of moDCs and the complement system through TF expression in a hypercoagulable state under inflammatory conditions and demonstrate the suppressive effects of C1 inhibitor on moDC-associated hypercoagulation.     

Thermoreversible gelation polymer induces the emergence of hepatic stem cells in the partially injured rat liver

Focal injury of the adult liver causes formation of granulomatous tissue and fibrosis. When thermoreversible gelation polymer (TGP) was applied to such defects of the rat liver, complete recovery of hepatic tissues was observed without granulation. We analyzed the mechanism of the regeneration. TGP is a chemically synthesized biocompatible polymer material whose sol-gel transition is reversible by changing the temperature. Cooled TGP was poured into a penetration lesion of the rat liver. Immunohistochemistry and polymerase chain reaction were carried out using tissues and cultured cells isolated from ductular structures. Immunocytochemical and ultrastructural analyses were also conducted. Seven days after TGP treatment, ductular reactions were observed around the wound and ductules elongated to the injured area. Cells in the structures were alpha-fetoprotein (AFP) positive, albumin+, CK19+, c-Kit+, and Thyl+. Hepatocyte-like cells possessing glycogen appeared around the tips of the ductules from day 9. The defect was completely replaced with hepatocytes by day 28. Cells isolated from the ductules expressed Musashi-1, c-Kit, Thyl, AFP, albumin, transferrin, connexin 43, and CK19. When the cultured cells were covered by TGP, they rapidly proliferated to form colonies, whereas without TGP cells gradually died. Morphologically and ultrastructurally the cells were similar to hepatocytes. They expressed not only albumin and transferrin but TAT, CYP2E1, and CCAAT/enhancer binding protein a. Some cells formed bile canaliculus-like structures. In conclusion, TGP may trigger the initiation of hepatic stem cells in biliary ductules, and stem cell activation may occur even in the regeneration of the normal liver.     

Complications of permanent makeup procedures for the eyebrow and eyeline

Japan is one of the few countries that consider the application of permanent makeup a medical procedure, and only doctors and nurses are allowed to perform this procedure. Studies on the safety and esthetic outcomes of permanent makeup procedures are not available, although there are studies that report allergies and other complications associated with permanent makeup. Thus, we aimed to study the complications and esthetic outcomes of permanent makeup.We surveyed clients who underwent permanent eyebrow or eyeline makeup procedures at the Shibuya Mori Clinic between November 2016 and March 2020 using a paper-based questionnaire. The permanent makeup procedures involved inorganic pigments, such as iron oxide and titanium dioxide. The questionnaire consisted of 2 parts: the first part asked whether the clients had experienced persistent redness, itching, swelling, infection, or any other complications (multiple answers possible). The second part used a 5-point Likert scale to rate the clients’ satisfaction with the color, shape, and overall appearance of their permanent makeup. We retrospectively studied the clients’ responses to survey items.A total of 1352 clients participated in the survey. The median period between the procedure and survey response was 15 days. Overall, complications were reported in 12.1% of cases. The most common complication for each type of procedure was itching for eyebrow procedures (8.2%) and swelling for eyeline procedures (13.2%). Infections were reported in 3 cases (0.2%). None of the post-procedure symptoms persisted until the time of this study. The Likert scale measurements revealed that 89.6% of subjects were satisfied with the aesthetic outcome of their permanent makeup procedure(s).We believe that all symptoms observed in this study were due to needle insertion. No allergies were observed, and the infection rate was quite low (0.2%). Thus, our results suggest that permanent makeup procedures are safe and are associated with high client satisfaction. We must note that the appropriate environment, equipment, and techniques are important prerequisites.     

Slow-metabolizing ADH1B and inactive heterozygous ALDH2 increase vulnerability to fatty liver in Japanese men with alcohol dependence

Background

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984, His48Arg) and aldehyde dehydrogenase-2 (ALDH2; rs671, Glu504Lys) affect body weight, body fat, and lipid metabolism in individuals with alcohol dependence, and the aim of this study was to identify their determinants in relation to the development of fatty liver.

Methods

We evaluated associations between the presence of fatty liver and ADH1B and ALDH2 genotypes and other factors in 1604 Japanese men who had been admitted for treatment of alcohol dependence.

Results

Fatty liver was diagnosed when ultrasonography showed both hepatorenal contrast and liver brightness. Age-adjusted usual alcohol intake did not differ according to ADH1B or ALDH2 genotypes. A multivariate analysis showed that the adjusted odds ratio (OR, 95% confidence interval) of slow-metabolizing ADH1B Arg/Arg carriers was 1.61 (1.27–2.03) for fatty liver and 1.82 (1.37–2.41) for fatty liver with deep attenuation in comparison with the ADH1B His/Arg or His/His carriers, and that the OR of inactive heterozygous ALDH2 Glu/Lys carriers was 1.43 (1.08–1.91) for fatty liver and 1.84 (1.31–2.59) for fatty liver with deep attenuation in comparison with the ALDH2 Glu/Glu carriers. Younger age, shorter interval between the last drink and the ultrasound examination, larger body mass index, and absence of cirrhosis were identified as other positive determinants for fatty liver.

Conclusions

The ADH1B Arg/Arg genotype and the ALDH2 Glu/Lys genotype were positive determinants of fatty liver in the subjects. These results suggest that slow ethanol and acetaldehyde metabolism accelerates the development of alcoholic fatty liver in heavy drinkers.

     

Resistance to the anti-proliferative effect of IL-1 on human melanoma cell line is associated with endogenous production of IL-1 and IL-6

A human melanoma cell line (A375–6) became resistant to the anti-proliferative effect of human IL-I after a long period of culture. Two stable resistant sub-clones were obtained, and the mechanism of the IL-I resistance was investigated. Resistant cells, but not sensitive cells, appeared to produce constitutiveiy IL-I activity. The activity was neutralized by anti-IL-I a antibody but not by anti-IL-I β antibody. Resistant cells expressed IL-I α but not IL-Iβ mRNA. Therefore, the resistant cells appeared to produce IL-β α. mRNA for IL-I receptor antagonist (IL-I Ra) was not detected in resistant cells, indicating that the resistance is not attributable to IL-IRa. These resistant cells were also resistant to the anti-proliferative effect of human IL-6, but not to that of human TNF. Resistant cells appeared to produce constitutively IL-6 more than sensitive cells, and IL-6 production both in sensitive and in resistant cells was augmented by exogenous IL-I. Furthermore, constitutive production of IL-6 in resistant cells was inhibited by IL-I Ra. Type I IL-I receptor (IL-IR) mRNA was expressed equally in resistant and sensitive cells. These data indicate that the resistance is not the result of loss of functional IL-IR and that IL-I induces IL-6 in an autocrine manner. It is, therefore, conceivable that endogenous IL-I and IL-6 contribute to IL-I resistance.     

Low Expression of Adhesion Molecules in a Case of Cutaneous T-cell Lymphoma

A case of cutaneous T-cell lymphoma (CTCL) with low expression of the adhesion molecules lymphocyte function-associated antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1), and very late antigen-4 (VLA-4) is described. The patient was a 90-year-old man with red round homogeneous tumors on his scalp, trunk, and extremities. He had no history of definite erythema or plaque stage. A biopsy sample taken from a tumor revealed massive infiltration of atypical lymphocytes in the reticular dermis and subcutis with a definite clear zone. The atypical lymphocytes were medium-sized with slightly convoluted nuclei. Immunohistochemically, the infiltrates showed the phenotype of so-called memory T cells. On the basis of these features, the case was diagnosed as CTCL. Expression of LFA-1, ICAM-1 and VLA-4 on the infiltrates was 9%, 13% and 11%, respectively, which is much lower than that in classic mycosis fungoides. This finding suggests that loss of these adhesion molecules may contribute to loss of epidermotropism in the advanced stage of CTCL.