Sequence-dependent Termination of Mammalian DNA Polymerase Reaction by a New Platinum Compound, (–)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) Monohydrate

We examined the mechanisms of the inhibition of DNA synthesis by a new platinum compound, (-)-( R )-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) monohydrate (DWA-2114R), a derivative of the antitumor drug cis- diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA-2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose-dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second-strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase α were strongly arrested at guanine-guanine sequences (GG). Stop bands were also observed at adenine-guanine sequences (AG) guanine-adenine-guanine sequences (GAG) and mono-guanine sequence (G). Calf testis DNA polymerase β was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.     

Excessive rapid palatal expansion with Latham appliance for distal repositioning of protruded premaxilla in bilateral cleft lip and alveolus.

OBJECTIVE: This article reports a case of bilateral cleft lip and alveolus (BCLA) for which excessive rapid palatal expansion with a Latham appliance was performed for preoperative alignment of the protruded premaxilla. Postoperative changes of maxillary width were investigated with serial plaster casts. PATIENT AND RESULTS: A 3-month-old girl presented with complete BCLA in which the premaxilla was markedly protruded. Preoperative alignment of the protruded premaxilla with a Latham appliance was planned to facilitate primary lip repair. The appliance was placed when the patient was 4.5 months old. The necessary palatal expansion was estimated to be 7.0 mm in order to move the premaxilla backward into the ideal position. After palatal expansion and posterior repositioning of the protruded premaxilla, the primary operation, including cheiloplasty and gingivoperiosteoplasty, was performed when the patient was 7 months old. Excessive maxillary expansion might be a cause of transverse maxillomandibular discrepancy. Measurement with serial plaster casts demonstrated that maxillary widths increased from 42.3 mm pretreatment to 49.0 mm after orthopedic treatment but relapsed markedly to 43.5 mm at 3 months after the primary operation. Therefore, the net change of maxillary widths was only 1.2 mm. After alignment of the protruded premaxilla, tension-free soft tissue repairs were performed, and a harmonious alveolar arch was obtained without change in maxillary width. CONCLUSION: These results indicate that this method is useful for preoperative management of BCLA with protruded premaxilla.     

A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension

Summary The pathogenesis of diabetic cardiomyopathy is unknown. The synergistic, or enhanced, effect of hypertension on pathological changes in the heart of diabetic patients has been highly suspected. The purpose of this study was to evaluate the myocardial changes related to diabetes mellitus with and without hypertension, using biopsy specimens. We examined the ultrastructural changes in biopsy specimens of the endomyocardium obtained from 25 patients. They were divided into four groups: controls without hypertension or diabetes mellitus (n=6), and patient with hypertension (n=3), diabetes mellitus (n=8), and diabetes with hypertension (n=8). The diabetic patients showed nearly normal or mildly depressed systolic left ventricular function. Ultrastructural pictures were analyzed for thickening of the capillary basement membrane, presence of toluidine blue-positive materials (i.e., materials showing metachromasia) in the myocytes, size of myocytes, and interstitial fibrosis. The thickening of the capillary basement membrane, the accumulation of toluidine blue-positive materials, and interstitial fibrosis were all significantly greater in the patients with diabetes mellitus compared to the control subjects. The myocytes tended to be small (cell atrophy) in the diabetes group. Although these pathological changes in the heart were characteristic of diabetic patients, irrespective of the presence or absence of hypertension, the presence of hypertension increased the pathological changes of myocardial cells as well as abnormality in the capillary vessels in patients with diabetes mellitus. Alterations in the myocardial cells and capillaries, caused by diabetes mellitus, may lead to myocardial cell injury and interstitial fibrosis and, ultimately, to ventricular systolic and diastolic dysfunction, especially when the diabetes is accompanied by hypertension.     

Comparative study of functional outcomes of three laparoscopic intestinal surgical procedures

ObjectivesLaparoscopic abdominal surgery (LS) has been prevailing over open surgery (OS). However, its functional outcomes in the aging generation have not been sufficiently examined. We compared changes in physical status and earlier resumption of oral intake between LS and OS.MethodsUsing the Japanese administrative database, we matched variables affecting LS and compared them between LS and OS patients. During the 6-month period from July to December of 2006–2010, we examined the data from data from surviving patients of ≥15 year old who underwent isolated gastrectomy, colectomy, or anterior resection. Functional status was estimated by the Barthel index (BI) at admission and discharge. Outcomes were postoperative complications, BI deterioration, change in BI, and day of recommencing postoperative oral intake.ResultsWe identified 30,763 gastrectomies (laparoscopic: 7297), 31,958 colectomies (laparoscopic: 9364), and 12,545 anterior resections (laparoscopic: 4351). Variation in LS indications was observed in patient and hospital mixes. Among the paired-matched gastrectomy, colectomy, and anterior resection groups, LS was associated with fewer complications and earlier recovery of postoperative oral intake. Laparoscopic anterior resection (LAR) and colectomy were associated with less frequent BI deterioration. Longer operative time was associated with more complications, which then influenced BI deterioration in patients who underwent anterior resection.ConclusionsShorter operative time for LAR was associated with less functional deterioration than for laparoscopic gastrectomy and colectomy. Physicians should consider the appropriate indications for LS by concurrently avoiding unnecessary longer operations and their associated complications. More investment in teaching the skills necessary for LAR is recommended.     

Comparing outcomes of nonoperative treatment for adhesive small bowel obstruction with and without antibiotics

IntroductionSome clinicians administer antibiotics in adhesive SBO treatment to prevent bacterial translocation without evidence confirming reduced sepsis and mortality. We aimed to evaluate the effectiveness of preventive antibiotic administration in nonoperative treatment of adhesive small bowel obstruction (SBO) in a retrospective study.MethodsUsing a Japanese national inpatient database, we identified 114,786 eligible patients with adhesive SBO and divided patients into a group who did not receive intravenous antibiotics in the initial 2 consecutive days after admission (control group, n = 71,666) and a group who received intravenous antibiotics ≥2 days after admission (antibiotic group, n = 43,120). To compare the in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, length of stay, and total costs between the two groups, we performed instrumental variable analyses to adjust for measured and unmeasured confounding factors.ResultsOverall, in-hospital mortality was 2.2%, and the occurrence of sepsis was 0.8%. In the instrumental variable analyses, no significant differences were found for in-hospital mortality, occurrence of sepsis, septic shock, Clostridioides difficile colitis, or total hospitalization costs. The antibiotic group showed a longer length of stay than the control group (coefficient, 1.9 days; 95% confidence interval, 0.6–3.2).ConclusionsIn this large nationwide cohort of patients with adhesive SBO, we found no benefit regarding preventive antibiotic administration in nonoperative treatment; however, antibiotic administration was associated with a longer hospital stay. These results did not support routine administration of antibiotics at admission to prevent bacterial translocation.     

Length of mechanical restraint following haloperidol injections versus oral atypical antipsychotics for the initial treatment of acute schizophrenia: A propensity-matched analysis from the Japanese diagnosis procedure combination database

Differences in effectiveness between haloperidol injection and oral atypical antipsychotics in the acute-phase treatment of schizophrenia are not well examined. We retrospectively investigated whether these treatment options affected the length of mechanical restraint. We used the Japanese Diagnosis Procedure Combination Database to identify schizophrenia patients who were involuntarily hospitalized and receiving mechanical restraint between July and December, 2006–2009. Data included patient demographics, use of antipsychotics, and number of days on which patients underwent mechanical restraint. Propensity score matching was performed to compare the number of days of mechanical restraint between the haloperidol injection group and the oral atypical antipsychotics group. We used survival analysis to examine whether the initial difference in treatment affected the number of days of mechanical restraint. Cox regression was performed to compare the concurrent effects of various factors. Among 1731 eligible patients, 574 were treated with haloperidol injections and 420 with atypical antipsychotics. Matching produced 274 patients in each group. Cox regression analysis showed that the initial therapeutic agents did not significantly affect the number of days of mechanical restraint. The results indicate that atypical antipsychotics were as effective as haloperidol injections in the acute-phase treatment of schizophrenia.     

Impact of new efficacy information on sales of antihypertensive medicines in Japan and Sweden

Objectives

The generic substitution of medicines has been introduced in Europe since the 1990s to increase price competition and the use of cheaper equivalents. Patent expiry is assumed to be associated with changes in sales patterns, particularly when combined with generic substitution. Other changes have been observed when prescribers obtain new information on drug safety and efficacy of medicines. This article examines to what extent patent expiry and new medical information on efficacy influence the pharmaceutical sales patterns of antihypertensive medicines in Japan and Sweden.