Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus.

PURPOSE: This study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database. METHODS: We analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors. RESULTS: After propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, - 3.8 [95% CI - 4.7 to - 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors. CONCLUSIONS: Our analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

Phenotypic modulation of smooth muscle cells in lymphoedema.

BACKGROUND: Lymphoedema is a debilitating progressive condition that is frequently observed following cancer surgery and severely restricts quality of life. Although it is known that lymphatic dysfunction and obstruction underlie lymphoedema, the pathogenic mechanism is poorly understood. Smooth muscle cells (SMCs) play pivotal roles in the pathogenesis of various vascular diseases, including atherosclerosis. OBJECTIVES: We analysed SMCs in lymphatic vessels from the lymphoedematous legs of 29 patients. METHODS: Expression of smooth muscle α-actin (SMαA) and smooth muscle myosin heavy chain (SM-MHC) isoforms SM1 and SM2 was investigated using immunohistochemistry. RESULTS: Compared with normal lymphatic vessels, all affected lymphatic vessels in chronic lymphoedema showed marked wall thickening. In addition to increases in the numbers of rows of SMαA(+) SM1(+) SMCs in the tunica media, SMCs were also observed in the subendothelial region (tunica intima). While most intimal and medial cells were positive for SMαA and SM1, staining for SM1 and particularly SM2, a marker of mature SMCs, progressively declined in lymphatic vessels in increasingly severe lymphoedema lesions. Consequently, the SM1(+) and SM2(+) cell fractions were significantly reduced in the tunica media and intima of lymphatic vessels. CONCLUSIONS: These observations indicate that the lymphatic tunica media and tunica intima consist mainly of phenotypically modulated SMCs, and that SMCs play a key role in the development of lymphoedema.

[Colopleural fistula caused by recurrence of gastric cancer; report of a case].

Perforation of colon into the pleural space without diaphragmatic hernia is extremely rare. This report illustrates a case of pneumo-pyothorax caused by perforation of metastatic tumor of the transverse colon of a 67-year-old woman with a history of total gastrectomy and splenectomy for advanced gastric carcinoma 4 years before. The patient was admitted to our hospital presenting with fever and dyspnea, which subsided after a thoracic drainage. Cultures of drained effusion revealed Escherichia coli, Klebsiella and Bacteroides. An emergent laparotomy for treatment of mechanical ileus 2 weeks after her admission disclosed a tumor obstructing the splenic flexure of the transverse colon, and a double-barreled colostomy was made. Pathologic examination of the tumors obtained from colon, mesocolon and the parietal peritoneum revealed poorly differentiated adenocarcinoma that was the same as her primary gastric cancer.

Clinicopathologic features of local and metastatic recurrences in primary lung adenocarcinoma.

We attempted to construct the contour of recurrence in primary lung adenocarcinoma with clinicopathologic variables based on data of 131 patients with completely resected primary lung adenocarcinoma. In univariate analysis, tumor size (more or less 3 cm in diameter), p-T, p-N, pathological stage, differentiation, ly factor and v factor were chosen for prognostic predictors. In multivariate analysis, v factor and p-N were independent variables of local recurrence and metastatic recurrence, respectively. The examination of significant correlation among clinicopathologic variables in terms of 5-year survival rates of patients showed that tumor size, p-T, ly factor and v factor were profoundly related to local recurrence, whereas ly factor, differentiation and p-N were linked to distant metastasis. We therefore examined an additive effect of tumor size, differentiation and vascular invasion on recurrence. The results demonstrated that neither local nor metastatic recurrences were found in patients with well differentiated adenocarcinoma less than 3 cm in diameter if vascular invasion was negative. We conclude that vascular (ly factor and v factor) is central to lung adenocarcinoma recurrence. The vascular invasion is a powerful predictor of recurrence in less than 3 cm diameter, well differentiated adenocarcinoma of the lung.

[The role of cardiac catheterization for diagnosis and treatment of pulmonary hypertension].

The role of the cardiac catheterization for diagnosis and treatment of pulmonary hypertension (PH) is very important. When mean pulmonary artery pressure increased more than 25 mmHg, then PH is defined. But this is measured accurately only by the catheterization. And we can discriminate the etiology of PH clearly by pulmonary capillary wedge pressure (Ppcw) or intra-cardiac shunt (L to R) by blood oxygen saturation step-up, and both parameters are obtained by this method. The etiology of PH is diagnosed as left sided heart failure, if Ppcw is increased more than 13 mmHg. PH is produced by congenital heart disease (ASD, VSD, PDA etc.), when the oxygen saturation step-up is recognized. And PH is induced by any pulmonary disease or pulmonary thrombo-embolism or collagen disease or liver cirrhosis or PPH, if Ppcw is normal and no oxygen step-up is recognized.

Reorganization of microtubules in the amitotically dividing macronucleus of tetrahymena.

We developed a modified immunofluorescence protocol that permitted visualization of microtubules inside the macronucleus of the ciliate Tetrahymena. Although the amitotically dividing macronucleus lacks a spindle, an elaborate system of microtubules is assembled inside the macronucleus and between the macronucleus and the cortex. Microtubules could not be detected inside the interphase macronuclei. The early stage of macronuclear division was associated with the assembly of short macronuclear microtubules that localized randomly. The intramacronuclear microtubules were subsequently organized in a radial manner. During elongation of the macronucleus, the distribution of macronuclear microtubules changed from radial to parallel. During constriction of the macronucleus, dense and tangled macronuclear microtubules were detected at the region of nuclear constriction. In the cytosol, microtubules were linking the macronucleus and cell cortex. During recovery after drug-induced depolymerization, microtubules reassembled at multiple foci inside the macronucleus in close proximity to the chromatin. We propose that these microtubules play roles in chromatin partitioning, macronuclear constriction, and positioning of the macronucleus in relation to the cell cortex.

Localization of microtubules during macronuclear division in Tetrahymena and possible involvement of macronuclear microtubules in 'amitotic' chromatin distribution.

The ciliated protozoa Tetrahymena contains two nuclei, a micronucleus and a macronucleus. In the vegetatively growing cell, the macronucleus divides amitotic while the micronucleus divides by mitosis. It has been indicated that microtubules are involved in macronuclear division and microtubules are observed to exist in the dividing macronucleus. To clarify the localization and the organization of microtubules in the amitotic dividing macronuclei, we used immunofluorescent staining technique. The microtubules were observed in the cytoplasm and macronucleus. The microtubules were organized and dynamically changed their distribution throughout the macronuclear division. We suggest a possibility that these microtubules are involved in 'amitotic' distribution of chromatin throughout the macronuclear division.

Macronuclear division and cytokinesis in Tetrahymena.

Tetrahymena contains a micronucleus and a macronucleus. The micronucleus divides with typical mitosis, while the macronucleus divides amitotically. Although the mechanism responsible for macronuclear division was previously unknown, we clarified the organization of microtubules during macronuclear division. The macronuclear microtubules dynamically changed their distribution in an organized way throughout the macronuclear division. The macronuclear microtubules and the cytoplasmic microtubules cooperatively carried out the macronuclear division. When the micronuclear division was finished, p85 appeared at the presumptive division plane prior to the cytokinesis. The p85 directly interacted with calmodulin in a Ca(2+)-dependent manner, and p85 and CaM colocalized to the division furrow during cytokinesis. Moreover, the Ca(2+)/CaM inhibitor, W7, inhibited the direct interaction between p85 and CaM, the localization of both proteins to the division plane, and the formation of the division furrow. Thus, Ca(2+)/CaM and p85 have important roles in initiation and progression of cytokinesis in Tetrahymena.

Molecular cloning and cell-cycle-dependent expression of the acetyl-CoA synthetase gene in Tetrahymena cells.

To identify transcriptionally regulated mediators associated with the cell cycle, we adopted the differential mRNA display technique for cell cultures of Tetrahymena pyriformis synchronized by cyclic heat treatment. One cDNA fragment that was expressed differently during synchronous cell division had a greatly decreased expression at 30 min after the end of heat treatment (EHT). Using this fragment as a probe, we isolated the full-length cDNA for T. pyriformis acetyl-CoA synthetase (TpAcs) which encodes a 651 amino acid polypeptide with a predicted molecular mass of 72.8 kDa. The deduced amino acid sequence of T. pyriformis ACS shows 42% sequence identity compared with that of Lysobacter sp. acetyl-CoA synthetase (ACS), an enzyme which catalyses the formation of acetyl-CoA from acetate via an acetyl-adenylate intermediate. The deduced sequence is also 41% and 40% identical compared with those of Pseudomonas putida and Coprinus cinereus ACS, respectively. The deduced sequence of T. pyriformis ACS also shares similar characteristics of the conserved motifs I and II in the ACS family. To further investigate the actions of the gene encoding this enzyme, mRNA expression was determined during the course of synchronized cell division in T. pyriformis. Northern blot results show that the mRNA level was dramatically decreased at 30 min after EHT prior to entering synchronous cell division (which occurs 75 min after EHT), suggesting that mRNA expression of the TpAcs was associated with the cell cycle and that the down-regulated expression of TpAcs at 30 min after EHT would be required for the initiation of the oncoming synchronous cell division in T. pyriformis.

Molecular cloning and cell-cycle-dependent expression of a novel NIMA (never-in-mitosis in Aspergillus nidulans)-related protein kinase (TpNrk) in Tetrahymena cells.

With the intention of investigating the signal-transduction pathway that mediates the cold-stress response in Tetrahymena, we isolated a gene that encodes a novel protein kinase of 561 amino acids, termed Tetrahymena pyriformis NIMA (never-in-mitosis in Aspergillus nidulans)-related protein kinase (TpNrk), by differential display from Tetrahymena cells exposed to temperature shift-down. TpNrk possesses an N-terminal protein kinase domain that is highly homologous with other NIMA-related protein kinases (Neks) involved in the control of the cell cycle. The TpNrk protein is 42% identical in its catalytic domain with human Nek2, 41% identical with mouse Nek1 and 37% with A. nidulans NIMA. In addition, TpNrk and these NIMA-related kinases have long, basic C-terminal extensions and are therefore similar in overall structure. In order to further explore the function of the TpNrk gene and the association of the cold stress with the cell cycle of Tetrahymena, changes of TpNrk mRNA were determined during the course of the synchronous cell division induced by the intermittent heat treatment. The level of TpNrk transcription increased immediately after the end of the heat treatment, with a peak at 30 min, and declined thereafter reaching the minimum level when nearly 80% of the cells synchronously entered cell division (75 min after the end of heat treatment). The accumulation of TpNrk mRNA starting from 0 min to 30 min after the end of the heat treatment was assumed to be a prerequisite for the start of synchronous cell division. These results suggest that TpNrk may have a role in the cell cycle of Tetrahymena, and that mRNA expression, at least, is under tight cell-cycle control.

Plasma brain natriuretic peptide as a parameter to assess efficacy of continuous intravenous infusion of prostacyclin (epoprostenol) to treat severe primary pulmonary hypertension: a case report.

Continuous intravenous infusion of prostacyclin (epoprostenol) as a treatment for primary pulmonary hypertension (PPH) definitely improves the patient's quality of life, but few accurate parameters have been found to evaluate the efficacy of the treatment. We observed a patient with severe PPH whose plasma brain natriuretic peptide (BNP) level changed significantly as her condition and symptoms changed. Plasma BNP may be considered as one of the parameters for assessing the efficacy of prostacyclin treatment.