The Impact of Tofogliflozin on Physiological and Hormonal Function, Serum Electrolytes, and Cardiac Diastolic Function in Elderly Japanese Patients with Type 2 Diabetes Mellitus.

The sodium glucose transporter 2 (SGLT2) inhibitor tofogliflozin is a glucose-lowering drug that causes the excretion of surplus glucose by inhibiting SGLT2. Because of tofogliflozin's osmotic diuresis mechanism, patients' serum electrolytes, body fluid levels, and cardiac function must be monitored. We retrospectively analyzed the cases of 64 elderly Japanese patients with type 2 diabetes mellitus (T2DM) who received tofogliflozin for 3 months. Their HbA1c, serum electrolytes (sodium, potassium, chloride), hematocrit, brain natriuretic peptide (cardiac volume load marker) and renin and aldosterone (RAA; an index of regulatory hormones involved in body fluid retention) were continuously monitored during the investigation period. Renal function and cardiac function (by echocardiography) were assessed throughout the period. HbA1c significantly decreased (ß1=-0.341, p<0.0001, linear regression analysis [LRA]). Most of the hormonal, electrolyte, and physiological parameters were maintained throughout the study period. In these circumstances, E/e' tended to decrease (ß1=-0.382, p=0.13, LRA). Compared to the baseline, E/e' was significantly decreased at 1 and 3 months (p<0.01, p<0.05). In the higher E/e' group (E/e'≥10, n=34), E/e' decreased significantly (ß1=-0.63, p<0.05, LRA). ΔE/e' was correlated with body-weight change during treatment (r=0.64, p<0.01). The 3-month tofogliflozin treatment improved glycemic control and diastolic function represented by E/e' in T2DM patients, without affecting serum electrolytes, renal function, or RAA. No negative impacts on the patients were observed. Three-month tofogliflozin treatment lowered glucose and improved cardiac diastolic function.

A new predictive tool consolidating CURB-65 with procalcitonin and albumin to assess short-term mortality in hospitalized elderly patients with infectious disease: A retrospective study of a patient cohort.

BACKGROUND: Hospitalized elderly patients are often at risk of life-threatening infectious diseases such as pneumonia and urinary tract infection, thus diagnostic tools for bacterial infections are demanded. We developed a new predictive tool consolidating modified CURB-65, procalcitonin (PCT) and albumin (Alb). METHOD: This is a retrospective study. Modified CURB-65 (mCURB-65) score, PCT, Alb, and various cardiovascular/respiratory/renal functions were measured. Survival analyses were conducted to assess 30-days mortality of elderly patients using mCURB-65 score, PCT and Alb. The consolidated scores were compared with the number of patients died. RESULTS: There were 445 elderly patients included. Kaplan-Meier survival curves showed significant differences between the high and low groups of mCURB-65, PCT and Alb (log-rank test, P < .001). Cox proportional regression showed that the hazard ratios (95% confidence intervals) for high mCURB-65, high Alb, and high PCT were all significant, 1.95 (1.24-3.05), 0.50 (0.32-0.77), and 2.09 (1.32-3.31), respectively. The consolidated scores showed tendency of increase with proportion of the number of patients died. CONCLUSIONS: The consolidated score consisted of mCURB-65, PCT and Alb can be a useful tool to predict short-term mortality of the hospitalized elderly patients with infectious disease.

Effects of tofogliflozin on adrenocorticotropic hormone, renin and aldosterone, and cortisol levels in elderly patients with diabetes mellitus: A retrospective study of a patient cohort.

ABSTRACT: Adrenocorticotropic hormone (ACTH) and cortisol reportedly play a role in glycemic control in patients with type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains controversial. We retrospectively investigated the effect of tofogliflozin on serum ACTH and cortisol levels in elderly patients with T2DM.Patients received 20 mg tofogliflozin daily for 3 months. Serum ACTH and cortisol levels were measured at baseline, as well as after 1 month and 3 months of tofogliflozin therapy.Serum ACTH levels were significantly reduced 3 months after tofogliflozin treatment (P < .01). Additionally, serum cortisol levels were reduced 3 months after tofogliflozin treatment, demonstrating borderline significance (P = .05). The higher body mass index (BMI; ≥25 kg/m2) group showed higher ACTH and cortisol levels than the lower BMI (<25 kg/m2) group, with borderline significance (P = .05). Renin levels were significantly increased 1 month after treatment (P < .05), maintaining serum aldosterone levels in parallel with the extracellular fluid.Our findings suggested that tofogliflozin decreased both serum ACTH and cortisol levels, with higher levels observed in the high BMI group. Tofogliflozin increased serum renin levels while maintaining serum aldosterone and extracellular fluid levels. Collectively, tofogliflozin could affect the hypothalamic-pituitary-adrenal pathway in patients with T2DM, especially in the low BMI group.

Intracranial malignant solitary fibrous tumor metastasized to the chest wall: A case report and review of literature.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare fibroblastic mesenchymal neoplasm that affects spindle cell soft tissues with broad-spectrum biological behavior; it is predominantly benign, and rarely metastasizes. SFT occurs mainly in the tissue structure of the serosa in the pleura and the thorax, and can be found throughout the body, though extra-thoracic localization, including the cephalic region, is un-common. We reported the first case of intracranial malignant SFT metastasized to the chest wall. CASE SUMMARY: An 81-year-old Japanese man was referred to our hospital due to progressive gait disturbance and appetite loss. His medical history included partial resection due to brain tumor, four times, and 50-Gray radiation therapy at another hospital, starting when he was 74 years old. An unenhanced head computed tomography (CT) scan revealed an 8 cm × 5.1 cm × 6.5 cm mixed-density mass at the left frontal lobe, accompanying a midline shift, and an unenhanced chest-abdomen CT scan revealed a 6 cm × 4.1 cm × 6.5 cm low-density mass in the left chest wall. A CT-guided percutaneous lung biopsy was performed, and the pathological findings were SFT corresponding to brain tumor. Finally, the correct diagnosis of his brain tumor in history of past illness revealed to be SFT, and the unremovable tumor, namely present brain lesions enlarged and metastasized to the chest wall. We established a definitive diagnosis of intracranial malignant SFT metastasized to the chest wall. We notified him and his family of the disease, and offered palliative care. He passed away on the 29th hospital day. CONCLUSION: This case suggests the need for careful, detailed examination, and careful follow-up when encountering patients presenting with a mass.

Gender Differences in Cardiac Function Following Three-Month Administration of Tofogliflozin in Patients With Diabetes Mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at increased risk for impairment in heart failure and diastolic relaxation while preserving ejection fraction (EF). Recently, several sodium glucose cotransporter-2 (SGLT2) inhibitors have demonstrated to decrease cardiovascular disease (CVD) events in elderly diabetic patients, although gender difference in the effect of SGLT2 inhibitors is unknown. The objective of the present study was to evaluate gender difference in the effect of tofogliflozin, one of the SGLT2 inhibitors, on CVD function in patients with diabetes mellitus. METHODS: This was a retrospective study. Patients received 20 mg of tofogliflozin daily for 3 months. EF, ratio of early filling to atrial filling (E/A), a change in mitral inflow E and mitral e' annular velocities (E/e'), left atrial dimension (LAD) and maximal diameter of inferior vena cava (IVCmax), including various physiological parameters were measured between baseline, 1 month and 3 months after administration of tofogliflozin. Interaction between gender and time after administration was evaluated using mixed effect model. RESULTS: The results showed significant decrease in E/e' (P < 0.01) and significant interaction between time and gender in E/A (P < 0.01), following administration of tofogliflozin for 3 months. EF was constantly higher significantly in women (P < 0.01). CONCLUSION: It is concluded that 3-month administration of tofogliflozin decreased E/e' with gender difference in EF and E/A.

[Resection of Metastatic Lung Tumor with a Right Displaced Segmental Bronchus (B1+3);Report of a Case].

We experienced a resected case of metastatic lung tumor with a right displaced segmental bronchus (B1+3). The patient was an 82-year-old woman who had a history of surgery for transverse colon cancer. A chest computed tomography (CT) scan revealed a nodular shadow with an irregular margin( 3.1 cm in diameter) in the right upper lobe, which was suspected of a primary lung cancer. Chest CT and bronchoscopy revealed B1+3 displaced segmental bronchus. Thoracoscope-assisted right upper lobectomy was performed for diagnostic and therapeutic purposes. The pathological diagnosis was a metastatic lung tumor from the transverse colon cancer.

Effects of Tofogliflozin on Cardiac Function in Elderly Patients With Diabetes Mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at increased risk for impairments in diastolic relaxation and heart failure with preserved ejection fraction (EF). Recent clinical data suggest that several sodium glucose transporter-2 (SGLT2) inhibitors are found to reduce cardiovascular disease (CVD) events in elderly diabetic patients, but the effect of tofogliflozin, one of the SGLT2 inhibitors, on CVD is unknown. We retrospectively investigated the effect of tofogliflozin on cardiac function in elderly patients with T2DM. METHODS: Patients received 20 mg of tofogliflozin daily for 1 month. EF, ratio of early filling to atrial filling (E/A), a change in mitral inflow E and mitral e' annular velocities (E/e'), left atrial dimension (LAD) and maximal diameter of inferior vena cava (IVCmax) were measured between baseline and 1 month after the administration of tofogliflozin. RESULTS: Body weight, systolic and diastolic blood pressures significantly decreased, while renin and aldosterone level significantly increased after 1 month of tofogliflozin treatment. Most of the physiological parameters and the level of serum electrolyte did not change significantly. E/A, E/e' and LAD significantly decreased, while no significant changes were observed in EF and IVCmax. The interactions of E/e' between time, gender and age were not significant. CONCLUSION: The present study suggested that tofogliflozin improved left ventricular diastolic function irrespective of gender and age, while preserving IVC, renal function and electrolyte balance.

[Lung Adenocarcinoma Combined with Minute Pulmonary Meningothelial-like Nodule (MPMN) in Young Patient;Report of a Case].

We report a rare case of lung adenocarcinoma combined with minute pulmonary meningothelial-like nodule (MPMN) in a young adult. A 39-year-old woman was referred to our department for abnormal shadow of the right lower lobe. Chest computed tomography (CT) showed a mass shadow, 11 mm in size, in right S6. Since fluorodeoxyglucose-positron emission tomography (FDG-PET) demonstrated a lesion with FDG activity, with an increased uptake value of 2.2, this lesion was suspected to be a lung cancer. Wedge resection of right S6 was performed via thoracoscopy. The intraoperative pathological diagnosis was invasive lung adenocarcinoma, and additional right S6 segmentectomy and lymph node dissection (ND1a) was performed. The final pathological diagnosis of the tumor was adenocarcinoma of the lung, and MPMN was incidentally found by pathology in reseced specimen.

The effects of 12-month administration of tofogliflozin on electrolytes and dehydration in mainly elderly Japanese patients with type 2 diabetes mellitus.

OBJECTIVE: To assess the effect of 12 months of treatment with tofogliflozin on electrolytes and dehydration in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: This retrospective study involved mainly elderly patients with T2DM who had received tofogliflozin for 12 months. Data on glycated haemoglobin (HbA1c), serum electrolytes (sodium, potassium, chloride), haematocrit, estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN)/creatinine ratio were retrieved and analysed. RESULTS: Data from 69 patients (77% of whom were ≥65 years) showed that there was a significant reduction in HbA1c over the 12-month treatment period with tofogliflozin. However, the drug had no significant effect on levels of haematocrit, electrolytes, eGFR or BUN/creatinine ratio. CONCLUSION: This retrospective analysis of data from mainly elderly Japanese patients with T2DM showed that 12-month administration of tofogliflozin exhibited glucose-lowering capabilities with accompanying low risk of electrolyte abnormalities and dehydration.

ADRB2 gene polymorphism and emphysema heterogeneity can modulate bronchodilator response in patients with emphysema.

BACKGROUND: Genetic variation in the ß2-adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to ß2-agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies. METHODS: The BDR (induced by 20 µg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from -100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema. CONCLUSION: Combination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of ß2-adrenergic receptor agonist treatment in patients with COPD and emphysema.

p53 Signaling Pathway Polymorphisms Associated With Emphysematous Changes in Patients With COPD.

BACKGROUND: The p53 signaling pathway may be important for the pathogenesis of emphysematous changes in the lungs of smokers. Polymorphism of p53 at codon 72 is known to affect apoptotic effector proteins, and the polymorphism of mouse double minute 2 homolog (MDM2) single nucleotide polymorphism (SNP)309 is known to increase MDM2 expression. The aim of this study was to assess polymorphisms of the p53 and MDM2 genes in smokers and confirm the role of SNPs in these genes in the pathogenesis of pulmonary emphysema. METHODS: This study included 365 patients with a smoking history, and the polymorphisms of p53 and MDM2 genes were identified. The degree of pulmonary emphysema was determined by means of CT scanning. SNPs, MDM2 mRNA, and p53 protein levels were assessed in human lung tissues from smokers. Plasmids encoding p53 and MDM2 SNPs were used to transfect human lung fibroblasts (HLFs) with or without cigarette smoke extract (CSE), and the effects on cell proliferation and MDM2 promoter activity were measured. RESULTS: The polymorphisms of the p53 and MDM2 genes were associated with emphysematous changes in the lung and were also associated with p53 protein and MDM2 mRNA expression in the lung tissue samples. Transfection with a p53 gene-coding plasmid regulated HLF proliferation, and the analysis of P2 promoter activity in MDM2 SNP309-coding HLFs showed the promoter activity was altered by CSE. CONCLUSIONS: Our data demonstrated that p53 and MDM2 gene polymorphisms are associated with apoptotic signaling and smoking-related emphysematous changes in lungs from smokers.

Sirt1 expression is associated with CD31 expression in blood cells from patients with chronic obstructive pulmonary disease.

BACKGROUND: Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34+ progenitor cells to examine whether these genes are associated with COPD development. METHODS: This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34+ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR. RESULTS: The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells. CONCLUSION: Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.

A three-microphone acoustic reflection technique using transmitted acoustic waves in the airway.

The acoustic reflection technique noninvasively measures airway cross-sectional area vs. distance functions and uses a wave tube with a constant cross-sectional area to separate incidental and reflected waves introduced into the mouth or nostril. The accuracy of estimated cross-sectional areas gets worse in the deeper distances due to the nature of marching algorithms, i.e., errors of the estimated areas in the closer distances accumulate to those in the further distances. Here we present a new technique of acoustic reflection from measuring transmitted acoustic waves in the airway with three microphones and without employing a wave tube. Using miniaturized microphones mounted on a catheter, we estimated reflection coefficients among the microphones and separated incidental and reflected waves. A model study showed that the estimated cross-sectional area vs. distance function was coincident with the conventional two-microphone method, and it did not change with altered cross-sectional areas at the microphone position, although the estimated cross-sectional areas are relative values to that at the microphone position. The pharyngeal cross-sectional areas including retropalatal and retroglossal regions and the closing site during sleep was visualized in patients with obstructive sleep apnea. The method can be applicable to larger or smaller bronchi to evaluate the airspace and function in these localized airways.

Effects of etidronate on calcification of scales and ribs in the goldfish, Carassius auratus.

Effects of etidronate on the calcification of scales and ribs were investigated in goldfish. Daily intraperitoneal injections of etidronate at doses of 1 and 10 mgP/kg body weight for 2 weeks inhibited calcification of ontogenic scales and ribs without affecting the accretion of organic matrices. Removal of some scales induced their regeneration within the two-week period. Their newly formed organic matrix was fully uncalcified in fish treated with 10 mgP/kg, whereas in those treated with 1 mgP/kg, the regenerating scales were only partially calcified. Daily administration of etidronate 10 mgP/kg resulted in an increase of body weight. These results suggested that the inhibitory effect of etidronate on the calcification of osseous tissues in mammals can be expected also on comparable tissues in fishes. An appropriate dose of etidronate that inhibits hard tissue calcification but not affects the body growth in fish seemed to exist between 1 and 10 mgP/kg.

Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome.

Several Long-Evans rat substrains carrying the phenotype of oculocutaneous albinism and bleeding diathesis are a rat model of Hermansky-Pudlak syndrome (HPS). The mutation responsible for the phenotype (Ruby) was identified as a point mutation in the initiation codon of Rab38 small GTPase that regulates intracellular vesicle transport. As patients with HPS often develop life-limiting interstitial pneumonia accompanied by abnormal morphology of alveolar type II cells, we investigated lung surfactant system in Long-Evans Cinnamon rats, one strain of the Ruby rats. The lungs showed conspicuous morphology of type II cells containing markedly enlarged lamellar bodies. Surfactant phosphatidylcholine and surfactant protein B were increased in lung tissues and lamellar bodies but not in alveolar lumen. Expression levels of mRNA for surfactant proteins A, B, C, and D were not altered. Isolated type II cells showed aberrant secretory pattern of newly synthesized [(3)H]phosphatidylcholine, i.e., decreased basal secretion and remarkably amplified agonist-induced secretion. [(3)H]phosphatidylcholine synthesis and uptake by type II cells were not altered. Thus Rab38-deficient type II cells appear to carry abnormality in lung surfactant secretion but not in synthesis or uptake. These results suggest that aberrant lung surfactant secretion may be involved in the pathogenesis of interstitial pneumonia in HPS.

A mutation in Rab38 small GTPase causes abnormal lung surfactant homeostasis and aberrant alveolar structure in mice.

The chocolate mutation, which is associated with oculocutaneous albinism in mice, has been attributed to a G146T transversion in the conserved GTP/GDP-interacting domain of Rab38, a small GTPase that regulates intracellular vesicular trafficking. Rab38 displays a unique tissue-specific expression pattern with highest levels present in the lung. The purpose of this study was to characterize the effects of Rab38-G146T on lung phenotype and to investigate the molecular basis of the mutant gene product (Rab38(cht) protein). Chocolate lungs exhibited a uniform enlargement of the distal airspaces with mild alveolar destruction as well as a slight increase in lung compliance. Alveolar type II cells were engorged with lamellar bodies of increased size and number. Hydrophobic surfactant constituents (ie, phosphatidylcholine and surfactant protein B) were increased in lung tissues but decreased in alveolar spaces, consistent with a malfunction in lamellar body secretion and the subsequent cellular accumulation of these organelles. In contrast to wild-type Rab38, native Rab38(cht) proteins were found to be hydrophilic and not bound to intracellular membranes. Unexpectedly, recombinant Rab38(cht) proteins retained GTP-binding activity but failed to undergo prenyl modification that is required for membrane-binding activity. These results suggest that the genetic abnormality of Rab38 affects multiple lysosome-related organelles, resulting in lung disease in addition to oculocutaneous albinism.

[Case of broncholithiasis lithoptysis occurring spontaneously after repeated pneumonia].

An abnormal chest shadow was pointed out in a 56-year-old woman in a health check in 2001. She had pulmonary tuberculosis at age 11. Because of repeated fever for the previous 2 years, she visited our hospital in 2003 and right upper lobe pneumonia was detected with a calcified nodule that completely obstructed the right upper lobe bronchus on CT. After admission, she spontaneously expectorated a stone. The composition of the stone was 57% calcium phosphate and 43% calcium carbonate. Radiological findings and the composition of the stone suggested that this broncholith was calcified bronchial mucus rather than a calcified lymph node that might have perforated into the airway. Bronchiectasis of the right B3 broncus was observed on CT scan after lithoptysis. Although the bronchiectasis was unchanged 2 years later, she had no symptoms, such as fever or cough.

Pulmonary surfactant transport in alveolar type II cells.

Pulmonary surfactant (PS) is a mixture of several lipids (mainly phosphatidylcholine; PC) and four apoproteins (A, B, C and D). The classical hypothesis of PS transport suggests that PS is synthesized in the endoplasmic reticulum and transported to the lamellar body (LB) via the Golgi apparatus. However, recent studies have raised questions regarding this single route. This study examined, independently, the intracellular trafficking route of three different components of PS, that is, PC, SP-A and SP-B. Alveolar type II cells were isolated from Sprague-Dawley rats or Japanese white rabbits. The cells were cultured with either [3H]choline or [35S]methionine/cysteine with or without brefeldin A, which disassembles the Golgi apparatus. LB was purified from disintegrated cells with sucrose density gradient centrifugation. [3H]PC was extracted from radiolabeled media, cells, and the LB fraction with Bligh-Dyer's method. [35S]SP-A or [35S]SP-B was immunoprecipitated from each sample with a specific antibody. [3H]PC was transported and stored to the LB via a Golgi-independent pathway. [35S]SP-A was transported to the Golgi apparatus, underwent glycosylation, and was then constitutively secreted. The secreted [35S]SP-A was re-uptaken into the LB. [35S]SP-B was transported and stored to the LB via the Golgi-dependent pathway. These results indicate that, rather than a single route, surfactant components take different pathways to reside in the LB. These different pathways may reflect the different nature and role of each surfactant component such as surface tension-lowering activity and innate host defense.

Fulminating onset type 1 diabetes with positivity for anti-GAD antibody and elevated pancreatic exocrine enzyme concentrations.

A 52-year-old man was admitted to our hospital for diabetic ketoacidosis. On admission, Hb(A1c) was 6.5%, anti-GAD antibody 10.3 U/ml, serum amylase 144 IU/l, lipase 169 U/l and elastase-I 1,000 ng/dl. There were no abdominal symptoms, and abdominal CT showed unremarkable findings. He was treated with intensive insulin therapy. After 1 month, urinary excretion of C-peptide was 3.8 microg/day. Serum pancreatic exocrine enzyme concentrations returned to normal after 3 months. After 10 months, anti-GAD antibody had become negative, but insulin therapy was still needed for glycemic control. This report concerns a case of autoimmune fulminating onset type 1 diabetes.