Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic β-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.     

Radiophotoluminescence phenomenon in copper-doped aluminoborosilicate glass

Radiophotoluminescence phenomena have been widely investigated on various types of materials for dosimetry applications. We report that an aluminoborosilicate glass containing 0.005 mol% copper exhibits intense photoluminescence in the visible region induced by X-ray and γ-ray irradiation. The luminescence is assigned to the 3d⁹4s¹ → 3d¹⁰ transition of Cu⁺. The proportionality of the intensity of the induced photoluminescence to the irradiation dose was confirmed up to 0.5 kGy using ⁶⁰Co γ-ray irradiation. Based on the spectroscopic results, a potential mechanism was proposed for the enhancement of the photoluminescence. The exposure to the ionizing radiation generates electron-hole pairs in the glass, and the electrons are subsequently captured by the Cu²⁺ ions, which are converted to Cu⁺ and emit the luminescence. For the glass containing 0.01 mol% copper, the pronounced enhancement of the photoluminescence was not observed because the reverse reaction, ie, the capture of the holes by the Cu⁺ ions, becomes prominent. The photoluminescence induced by the irradiation was stably observed for the glasses kept at room temperature and even for the glasses heat-treated at 150°C. However, the induced photoluminescence could be eliminated by the heat treatment at a temperature at 500°C, and the glass returned to the initial pre-irradiation state. The Cu-doped aluminoborosilicate glass is a potential candidate for use in dosimetry applications.     

Effects of the thermal history on the hydraulic properties of slags

Glasses with two composition in the CaO---Al₂O₃---SiO₂ system were prepared with different cooling conditions. Glass A has a eutectic composition of wollastonite-gehlenite-rankinite and glass B has that of wollastonite-gehlenite-anorthite. The effects of the thermal history on the structure and hydraulic properties were discussed. Effects of cooling rate on the physical and chemical properties of glasses are found to be different with chemical composition of glass. Cooling rate affects the hydraulic reactivity and crystallization temperature, especially in glass A, but scarcely affects the physical properties such as chemical shift of AlK and surface basicity of the glass.     

Rapid detection cytomegalovirus pneumonia in recipients of bone marrow transplant: evaluation and comparison of five survey methods for bronchoalveolar lavage fluid

To detect cytomegalovirus-associated interstitial pneumonia (CMV-IP) in recipients of BMT in its earliest stage, five CMV methods were assessed for their usefulness using bronchoalveolar lavage fluid as the test specimen. Of the 43 cases enrolled in the study, PCR was positive in 12 cases, shell vial in eight, culture in eight and cytology in three. There were no positive cases in in situ hybridization. Based on this result, the 43 cases were classified into four groups: Group 1, three cases: positive in PCR, shell vial and cytology; Group 2, five cases: positive in PCR and shell vial; Group 3, four cases: positive only in PCR; and Group 4, 31 cases: negative in all CMV tests. Cases in Group 1 were judged as having the highest risk of overt CMV-IP. They were successfully treated with a combination of ganciclovir and immunoglobulin. Group 2 was diagnosed as having active CMV infection and ganciclovir monotherapy was effective for these patients. Groups 3 and 4 were not given anti-CMV therapy, but they were free from CMV-related manifestations throughout the study. The sensitivity and specificity of each survey method for the detection of Groups 1 and 2 were 1.0 and 0.89 in PCR, 1.0 and 1.0 in shell vial, 0.88 and 1.0 in culture, and 0.38 and 1.0 in cytology. Similarly, the positive and negative predictive values were 0.67 and 1.0 in PCR, 1.0 and 1.0 in shell vial, 1.0 and 0.97 in culture, and 1.0 and 0.88 in cytology. Thus, CMV survey on bronchoalveolar fluid was thought to be useful in detecting post BMT CMV-IP in its earliest stage.     

Non-atherosclerotic acute myocardial infarction

AIM: The aim of the study is to analyse the benefits and risks of PEE in patients, cared for by a team with many years experience. PATIENTS AND METHODS: From 16. 2. 1988 until 31. 12. 1993 246 PEEs (229 gastrostomies, 6 duodenostomies, 7 jejunostomies, 4 attempts) were performed on 234 patients (56% male, 44% female, mean age 68.3 years). 117 patients had tumorous and 117 neurological diseases. We used the pull technique with the Fresenius Freka PEG-system. Analysis was performed using a standardised documentation sheet which was filled out until the end of tube feeding. In total, we registered 39,678 days of tube feeding, 4513 of which were in hospitalized patients. RESULTS: The mean intubation time was 192.6 days (maximum 1496). In 8 cases, the tube could be explanted before the patient was discharged; 68 patients were discharged to a nursing home and 71 patients were allowed to go home. The tube-independent hospital lethality was 36.64%. A PEE-specific lethality had not been registered. Complications arose in a total of 37 patients (15.04%), 4 of which were severe (1.63%) Fifty-nine patients (25.43%) reported short-term feelings of ill health (vomiting, diarrhoea, pain). CONCLUSION: PEE is an effective and low-risk method of long-term nutrition. The advantages are simple insertion, safe handling by patients and relatives/nursing staff and the low cost.     

Three-dimensional motion of the upper cervical spine in rheumatoid arthritis

Rheumatoid arthritis frequently contributes to instability of the upper cervical spine. Rotational instability of the upper cervical spine was evaluated in rheumatoid arthritis patients using biplanar x-ray photogrammetry. Three-dimensional cervical motion and the instantaneous axis of rotation of the atlas relative to the axis were evaluated in normal and rheumatoid arthritis patients during axial rotation in the horizontal plane. Anterior atlantoaxial subluxation did not increase during axial head rotation in either the atlantoaxial subluxation or the vertical subluxation groups, while the instantaneous axes of rotation were distributed posteriorly in the dens in the RA-normal group, but were widely scattered in the atlantoaxial subluxation group.     

Successful surgical repair for a patient with atrial septal defect and severe pulmonary hypertension--its surgical indication and prostaglandin E1 use for postoperative pulmonary hypertensive crisis

A 45-year-old woman with atrial septal defect and pulmonary hypertension was admitted for surgical repair. Cardiac catheterization data revealed pulmonary to systemic flow ratio (Qp/Qs) of 1.81, pulmonary artery pressure (PAP) of 82/30 mmHg and pulmonary vascular resistance (PVR) of 10.8 unit. Open lung biopsy was added to evaluate pulmonary vascular obstructive disease (PVOD) which was shown Heath-Edwards grade 3 PVOD. Following closure of the defect, PAP (systolic) exceeded momentarily systemic level after cardiopulmonary bypass. Prostaglandin E1 drip was remarkably effective to bring down PAP during early postoperative period. Although PAP has not been shown significant decrease on catheterization of one year after surgery, great symptomatic improvement has been achieved.     

Preoperative thermochemotherapy of oral cancer using magnetic induction hyperthermia (Implant Heating System: IHS)

This study investigated the impact of Difficulty Level and Type of Suggestion upon the durability of posthypnotic suggestion over an 8-week period. Seventy-eight highly susceptible subjects selected by both the Harvard Group Scale of Hypnotic Susceptibility: Form A (HGSHS:A) and Stanford Hypnotic Scale of Susceptibility: Form C (SHSS:C) were assigned to six groups (two levels of Difficulty x three Types of Suggestion). S's were tested for posthypnotic suggestion at 1, 3, 6, and 8 weeks. A 2 x 3 x 4 (Difficulty x Suggestion x Time) factorial ANOVA was conducted, with Time treated as a repeated-measure. The outcome variable at each time was either pass or fail for relevant suggestion. We found a significant Time effect, a significant Difficulty effect, and a significant Time x Difficulty interaction. Fewer subjects passed the difficult suggestions than passed the easy suggestions; fewer passed suggestions at a latter time; and the decay in pass rate was more pronounced for the easy suggestion condition, due largely to the higher initial pass rate. Type of Suggestion was not significant, nor were any of the other interactions. Clinical implications were discussed.