The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

Rapid and sensitive method for detection of Salmonella strains using a combination of polymerase chain reaction and reverse dot-blot hybridization.

We have developed a reverse dot-blot hybridization assay for detection of Salmonella using Salmonella-specific oligonucleotide probes designed from the base sequence of the 16S rRNA gene (rDNA). The target fragment of 16S rDNA was amplified, and labelled with biotin by the polymerase chain reaction. The amplified fragment was hybridized with the membrane-immobilized probe and the hybridization was detected by chemiluminescence. Amplified fragments from 24 different serovars of Salmonella hybridized with the probes, whereas those of species of Enterobacteriaceae, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus failed to hybridize. By this assay, it was possible to detect in the order of 10(4) bacteria in fish meat homogenate in 10 h.

[Patient's delay and doctor's delay in the primary treatment cases of pulmonary tuberculosis detected by subjective symptoms].

Delays in case finding were studied for the primary tuberculosis patients who were discharged from our hospital in 1987. Of 321 tuberculosis patients who were released from our hospital in 1987, 171 patients received primary treatment. Eighty one of them had been detected by their symptomatic visits. Patient's and doctor's delays tended to be longer in the cases of males than of females. For both males and females patient's delay tended to be longer in younger age group. Total delay until definite diagnosis by 50% and 80% of all diagnosed were 1.6 months, and 3.5 months respectively. Patients with total delay of more than three months were younger in age and were hospitalized longer than patients with total delay of less than 3 months. All cases with total delay of more than three months were smear positive.

[Repeated postoperative hypoglycemia in a woman with multiple pheochromocytomas].

A case of repeated postoperative hypoglycemia following removal of multiple pheochromocytomas in a non-diabetic 23-year-old woman is presented. Although the hypoglycemia did not occur after the first operation, it was recognized after the second and third operations. The blood sugar levels were 54 mg.dl-1 and 25 mg.dl-1, respectively, and continuous intravenous glucose infusion was necessary for about 15 hours postoperatively. This complication may be related to sudden withdrawal of catecholamines. Frequent monitoring of blood sugar level as well as cardiovascular system is important for perioperative management of pheochromocytoma.

[Effect of nafamostat mesilate on serum activities of pancreatic enzymes and plasma hormone levels].

To evaluate the effect of nafamostat mesilate, a potent protease inhibitor, on the pancreatic enzymes and the endocrine system in patients undergoing open-heart surgery with extracorporeal circulation, serum activities of amylase, trypsin, alpha 1-antitrypsin (alpha 1AT) and pancreatic secretory trypsin inhibitor (PSTI), and plasma levels of cortisol and catecholamines were measured. Seven patients (nafamostat group) received intravenous nafamostat mesilate 0.5 mg.kg-1.hr-1 during cardiopulmonary bypass (CPB). The remaining seven patients (non-nafamostat group) did not receive any protease inhibitor. Both groups showed the same changes in serum activities of pancreatic enzymes during CPB. In sera, the levels of amylase, trypsin and alpha 1AT decreased during CPB. Amylase and trypsin activities returned toward the preanesthetic levels after CPB, while alpha 1AT remained at lower levels. PSTI was unchanged during CPB. Plasma cortisol levels markedly increased during and after CPB, but there was no difference between nafamostat group and non-nafamostat group. Nafamostat group showed lower plasma dopamine levels and higher epinephrine levels compared with non-nafamostat group. The result suggests that nafamostat mesilate administered during CPB could not influence the changes in the activities of pancreatic enzymes. Further studies are needed to clarify the effect of this protease inhibitor on the endocrine system.

[An emergency operation for a Jehovah's Witness with ruptured thoracic saccular aneurysm].

A 49-year-old male "Jehovah's Witness" was transferred to our hospital with hypotension, abdominal pain, and abdominal distension, and a diagnosis of ruptured thoracic saccular aneurysm was made. He and his family insisted on having an emergency operation for his ruptured aneurysm without blood transfusion. After an intensive discussion among the patient, his family, surgeons, and the director of the hospital, we performed the operation without blood transfusion. The operation using cardiopulmonary bypass took about five hours under enflurane anesthesia, but he died of circulatory collapse fifteen hours after the end of operation. As there may be various opinions concerning how we should take care of Jehovah's Witness patients, we have to manage them case by case.

[The anesthetic management of patients in chronic renal failure for coronary artery bypass surgery without cardiopulmonary bypass].

We describe our experience with three patients in chronic renal failure who underwent coronary artery bypass surgery without cardiopulmonary bypass. Anesthesia was maintained with fentanyl and midazolam. Nitroglycerin and prostaglandin E1 were administered during the surgical procedure. When the coronary artery was clamped for the anastomosis of the graft, cardiac output and arterial pressure decreased in all cases. The patients were treated with ephedrine and dobutamine, which restored the hemodynamics. The important points for the anesthetic management for this operation are follows: the adequate administration of the coronary vasodilator, and attention to the change of hemodynamics on clamping the coronary artery.

[Effects of intravenous infusion of isosorbide dinitrate on hemodynamics during anesthesia and surgery].

Ninety nine patients with ischemic changes of the heart on preoperative and intraoperative ECG tracings were studied to evaluate effects of intravenous infusion of isosorbide dinitrate on hemodynamics during anesthesia and surgery. These patients ranging in ages from 24 to 80 years were administered intravenous isosorbide dinitrate at a rate of either 0.5 or 1 microgram.kg-1 x min-1 during anesthesia and surgery. Arterial blood pressure was not influenced with intravenous isosorbide dinitrate at the speed of 0.5 microgram.kg-1 x min-1 during anesthesia and surgery. The arterial pressure of the patients decreased slightly but significantly 30 min after the start of 1 microgram.kg-1 x min-1 of isosorbide dinitrate infusion, but it recovered to the control level at the end of administration of isosorbide dinitrate. Heart rate was unchanged with intravenous isosorbide dinitrate during anesthesia and surgery in both groups, except a mild increase at the end of isosorbide dinitrate infusion of 1 microgram.kg-1 x min-1. Arterial blood oxygen tension showed no decrease during the administration of isosorbide dinitrate and no adverse reactions associated with administration of the drug was detected in this study. Significant improvement of ischemic changes on ECG tracings were observed in about 25% of the patients who received 1 micrograms.kg-1 x min-1 of intravenous isosorbide dinitrate.

[Prolonged respiratory depression following general anesthesia in a patient with dystrophia myotonica].

A case of general anesthesia for a 52 year old female with previously undiagnosed dystrophia myotonica was reported. The patient was diagnosed as flaccid paralysis of the bilateral lower extremities but myotonic symptoms were not found preoperatively. The patient underwent duodenal resection to have a benign tumor removed. Anesthesia was induced with thiamylal 250 mg and pancuronium bromide 4 mg intravenously to facilitate tracheal intubation. Anesthesia was maintained with enflurane (0.6-1.0%) in nitrous oxide (50%) and oxygen (50%). The course of anesthesia was uneventful except for a transient hypotension of 80 mmHg systolic for about 10 minutes. The patient did not recover smoothly from anesthesia and prolonged apnea was observed. 90 minutes after the end of surgical procedure, spontaneous ventilation appeared. Then the tidal volume increased gradually but it still remained around 100-150 ml even 3 hours after the end of the operation. She was on ventilator and observed carefully. The endotracheal tube was removed four days after the operation. The patient was examined again by a neurologist and a final diagnosis of dystrophia myotonica was made. Prolonged recovery from anesthesia and postoperative respiratory depression observed in this patient was due to preoperatively undiagnosed dystrophia myotonica. A careful preoperative examination should be made to minimize possible complication related to anesthesia in the disease.

[Clinical study on total intravenous anesthesia with droperidol, fentanyl and ketamine--20. Summary of three thousand cases and the future of this anesthetic method].

Total intravenous anesthesia with droperidol, fentanyl and ketamine (DFK) was given to over three thousand patients during four years from April 1989 through March 1993. The patients ranged in age from three months to eighty seven years. They underwent surgical, orthopedic, gynecological, thoracic, plastic and otolaryngeal surgeries, but patients who underwent craniotomy and obstetric operations were excluded. None of them developed any serious complications primarily due to DFK. DFK has many advantages such as the broad safety margin for three agents employed in DFK, no accident by N2O, no air pollution, empty bowels, no increase in middle ear pressure etc, while this has disadvantages such as high blood pressure, slow awakening from anesthesia and unpleasant dreams. Calcium channel blockers are very effective for antagonizing high blood pressure, and rapid recovery from anesthesia can be easily obtained by reducing ketamine dose given and also by application of epidural block. Intraoperative dreams may be avoided by concomitant use of benzodiazepines. Thus we are convinced that DFK can be a good as well as convenient anesthetic method for clinical anesthesia.

[The effects of lowering of blood pressure on pain sensitivity in spontaneously hypertensive rats].

It has been reported that elevation of blood pressure produces a reduction in pain sensitivity. This study was designed to clarify the correlation in spontaneously hypertensive rats (SHR) between fall in blood pressure and pain sensitivity. In seven-weeks-old male SHR, the angiotensin converting inhibitor delapril (10 mg/kg/day) or calcium antagonist nifedipine (3 mg/kg/day) was administered orally every day for 8 weeks. Systolic blood pressure (SBP) pretreatment was significantly higher in the SHR than in normotensive Wistar-Kyoto (WKY) rats and pain sensitivity measured with the hot plate method was significantly lower in the SHR than in the WKY rats. Administration of both drugs produced a significant suppression of elevation of SBP, and produced a significant elevation of pain sensitivity. Furthermore, at 8 weeks after drug administration, urinary norepinephrine (UNE) significantly decreased and plasma beta-endorphin (beta-end) significantly increased. A significant correlation was noted between pain sensitivity and SBP and also between pain sensitivity and UNE. Of these, pain sensitivity was the more closely correlated to degree of change in UNE than to degree of change in SBP. It appears that elevation of pain sensitivity is due to suppression of the sympathetic nervous system by antihypertensive drugs, but not to elevation of beta-end levels. These data suggest that a fall in blood pressure through administration of delapril or nifedipine reverses decrease in pain sensitivity in SHR and that decrease in sympathetic tone plays an important role in the restoration of levels of sensitivity to pain.

[Clinical evaluation of prostaglandin E1 during anesthesia in non-elderly and elderly patients].

The effects of prostaglandin E1 (PGE1) on blood pressure during anesthesia and the postoperative changes in organ functions were examined and compared in 358 cases. Two hundred and eighty patients were under 64 years of age and 128 patients were over 65 years. It was possible to control blood pressure satisfactorily with PGE1 in both non-elderly and elderly groups. However in the elderly group, it was more difficult to control blood pressure with PGE1 under NLA as compared with enflurane anesthesia. In both groups, urinary flow increased during and after the administration of PGE1, and the livers and kidneys showed neither dysfunction nor deterioration after operation. We had very few incidences of side effects with this drug. PGE1 is also considered safe and useful for elderly people during and after surgery.