Contribution of itch-associated scratch behavior to the development of skin lesions in <Emphasis Type="Italic">Dermatophagoides farinae</Emphasis>-induced dermatitis model in NC/Nga mice

Recently, we have reported that the pathophysiological features of dermatitis induced by the repeated application with Dermatophagoides farinae (Df) extract ointment in NC/Nga mice were similar to those observed in the patients with atopic dermatitis. In the present study, we first examined whether the application of Df in other mouse strains could induce dermatitis. The repeated application of Df body (Dfb) ointment to the barrier-disrupted back of ICR, C57BL/6, and Balb/c mice did not cause any apparent skin lesions, although transient increase in serum immunoglobulin E (IgE) levels during antigen application was observed. On the other hand, in NC/Nga mice, dermatitis scores and serum IgE levels increased remarkably, and then these changes sustained for at least 10 days after stopping of antigen elicitation. Using NC/Nga mice, we investigated the contribution of scratching behavior to the development and maintenance of Dfb-induced dermatitis. In correlation with the increase in scratching behavior, erythema, hemorrhage, edema, scarring, erosion and excoriation were observed. Cutting off the hind toenails of mice exhibiting chronic skin lesions dramatically alleviated the dermatitis. From these findings, the onset of skin lesions and its chronically sustained course in Dfb-induced dermatitis in NC/Nga mice were closely associated with increased scratching behavior.     

Muscle energetics in short-term training during hypoxia in elite combination skiers

Four well-trained combination skiers were studied through pre- and post-training for the effects of short-term intermittent training during hypoxia on muscle energetics during submaximal exercise as measured by Phosphorus-31 nuclear magnetic resonance and maximal aerobic power ( O_2max). The hypoxia and training in the cold was conducted in a hypobaric chamber and comprised 60-min aerobic exercise (at an intensity equivalent to the blood lactate threshold), using a cycle ergometer or a treadmill twice a day for 4, consecutive days at 5°C, in conditions equivalent to an altitude of 2000 m (593 mm Hg). No change in O_2max was observed over the training period, while in the muscle energetics during submaximal exercise, the values of phosphocreatine/(phosphocreatine + inorganic phosphate) and intracellular pH were found to be significantly increased by training during hypoxia. During recovery, the time constant of phosphocreatine was found to have been significantly reduced [pre, 27.9 (SD 6.7) s; post, 22.5 (SD 4.7) s, P < 0.01]. The observed inhibition of phosphocreatine as well as that of intracellular pH changes after training during hypoxia and quicker recovery of phosphocreatine in submaximal exercise tests, may indicate improved oxidative capacity (i.e. a high adenosine 5-triphosphate formation rate) despite the short-term hypoxia training. Present address: Department Life Sciences, Univ. of Tokyo, Komaba 3-8-1, Meguro-ku 153, Japan     

B Lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.     

Use of sodium–glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus

Aim

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long‐term use of SGLT2 inhibitors in older patients with diabetes.

Methods

A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016.

Results

The mean age of the patients was 73.7 ± 10.0 years. During the follow‐up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow‐up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment.

Conclusions

In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108–114 .     

Incidence of malignancy in Japanese patients with rheumatoid arthritis

To determine the incidence of malignancy and site-specific malignancies in Japanese patients with rheumatoid arthritis (RA). In a prospective large observational cohort study named IORRA, 7,566 patients with RA were enrolled from April 2001 to April 2005 and were followed up to October 2005. Occurrence of malignancy was originally collected by patient reports of IORRA survey biannually from April 2001 to October 2005, and was confirmed by medical records. Standardized incidence rate (SIR) of the observed-to-expected cancer incidence and 95% confidence intervals (95% CI) were then calculated. Factors obtained at first enrollment in IORRA were assessed for association with risk of malignancy using the Cox proportional hazards model. A total of 177 malignancies in 173 patients (58 in men, 115 in women) were identified during the observation period of 25,567 person-years. The age- and sex-standardized incidence rate of malignancy was 437.1 (men, 706.8; women, 366.1) per 100,000 person-years. The SIR of malignancy was slightly excess (SIR 1.18, [95% CI 1.02–1.37]) in all patients, but 1.29 (95% CI 0.99–1.67) in men, and 1.13 (95% CI 0.94–1.36) in women. A significant excess of lymphoma (SIR 6.07, [95% CI 3.71–9.37]) and lung cancer (SIR 2.29, [95% CI 1.57–3.21]), whereas decreased incidence of colorectal cancer (SIR 0.49, [95% CI 0.26–0.83]), were found. Male gender and older age were identified as risk factors for malignancy. A slight excess in the incidence of overall malignancy and highly excess of lymphoma in Japanese RA patients was demonstrated.     

Localization of Na-K-ATPase in guinea-pig myocardium

The cytochemical distribution of Na-K-ATPase was demonstrated in the guinea-pig myocardium. The hearts were fixed with paraformaldehyde glutaraldehyde mixture, sections were incubated at room temperature in modified Ernst medium employing p-nitrophenyl phosphate as substrate and the tissue was processed for electron microscopy. The ATPase activity was localized in the subsarcolemmal cisterns, inner side of plasma membrane, T-tubules, free and junctional sarcoplasmic reticulum and capillary endothelium. The reaction product on the plasma membrane and T-tubules was inhibited by ouabain or by potassium deletion. However, the amount of precipitation in mitochondria, sarcoplasmic reticulum (free and junctional) and subsarcolemmal cisterns remained unaffected by ouabain or by potassium deletion. The enzyme reaction in the myocardium represents ouabain-sensitive, potassium-dependent ATPase.     

Is rabbit CLCA1 related to the basolateral Ca2+ -dependent Cl- channel of gastric parietal cells?

An expression of mRNA coding the calcium-activated Cl- channel-1 (CLCA1) in rabbit gastric parietal cells was examined to verify the possibility that the CLCA1 mediates housekeeping Cl- channels in the basolateral membrane. In whole-cell voltage-clamp experiments of rabbit parietal cells, A23187 (2 microM), a Ca2+ ionophore, activated the basolateral Cl- channels. The partial cDNA fragment of rabbit CLCA1 could be amplified from the total RNA of tracheal epithelium. A Northern blot analysis showed that rabbit CLCA1 mRNA of 3.4 kb is highly expressed in the tracheal epithelium, but not in the gastric parietal cells. Even in a more sensitive detection of rabbit CLCA1 mRNA by RT-PCR, no signal could be observed in the gastric parietal cells. These results suggest that the CLCA1 protein may not be a subunit of the housekeeping Ca2+ -dependent Cl- channel in the basolateral membrane of rabbit gastric parietal cells.     

Effect of dietary zinc deficiency on ischemic vulnerability of the brain

Deficiency of zinc, which modulates glutamate release, might increase ischemic vulnerability of the brain. We examined effects of dietary zinc deficiency for 2 weeks on ischemic vulnerability in several brain regions using dynamic positron autoradiography technique and [¹⁸F]2-fluoro-2-deoxy-d-glucose with rat brain slices. In the normal diet group, the cerebral glucose metabolic rate (CMRglc) was not significantly different from that of the ischemia-unloaded control even after the loading of ischemia for 45 min. However, in the zinc-deficient diet group, CMRglc was significantly lower than that of the ischemia-unloaded control after loading of ischemia for 45 min. With treatment of MK-801 (NMDA receptor antagonist) from the start of ischemia loading, CMRglc was not significantly different from that of the ischemia-unloaded control. These findings, obtained for all analyzed brain regions, suggest that dietary zinc deficiency increased ischemic vulnerability in the brain, and that glutamate might contribute to this effect through activation of the NMDA receptor.