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.     

Comparison of surgical and conservative treatment outcomes for type a aortic dissection in elderly patients

Background

In recent years, surgical outcomes have improved, and positive reports on surgery for type A aortic dissection (AAD) in the elderly are increasing. However, the difference between surgical and conservative treatments in the elderly remains unclear. Therefore, we conducted this study to determine whether surgery should be performed for Stanford (AAD) in elderly patients.

Methods

Data of patients aged 80?years or older who were hospitalized for AAD from April 2014 to March 2016 were extracted from the Japanese national inpatient database. Outcome measures were all-cause in-hospital death, stroke, acute kidney injury and tracheotomy, and composite adverse events (consisting of all-cause in-hospital death, stroke, acute kidney injury, and tracheotomy), and we compared them between surgical and conservative treatments using propensity score matching.

Results

The study cohort included 3258 patients, with 845 matched pairs (1690 patients) in the propensity score matching. All-cause in-hospital death was significantly lower in the surgical treatment group than in the conservative treatment group before and after matching (15.6% vs. 51.1%, p?<?0.001; 16.7% vs. 31.6%, p?<?0.001, respectively); however, there was no significant difference in composite adverse events after matching (36.0%, conservative vs. 37.2%, surgical; p?=?0.65), and adjusted odds ratio was 1.06 and 95% confidence interval was 0.86–1.29 (p?=?0.61) with reference to conservative treatment.

Conclusions

All-cause in-hospital death among elderly patients with AAD was significantly lower in patients treated surgically than in those undergoing conservative treatment. However, there was no significant difference between the two groups in the event-free survival, which is important for the elderly. These findings may be used in the consideration of treatment course for elderly patients with AAD.

     

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.     

Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six‐month‐old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure‐free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34‐positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon‐like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule‐like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.     

Severe liver injury associated with simeprevir plus pegylated interferon/ribavirin therapy in a patient with treatment-naïve genotype 1b hepatitis C virus: a case report

A second-generation direct-acting antiviral agent, simeprevir, now provides a new treatment option for hepatitis C virus (HCV) infection with good safety profile in combination with pegylated interferon and ribavirin. We herein report a rare case of severe liver injury under simeprevir plus pegylated interferon/ribavirin therapy. We initiated this therapy in a 65-year-old male with treatment-naïve genotype 1b HCV. On day 28, the patient’s HCV-RNA was successfully eliminated, and his liver function was fully restored. However, on day 49, the serum alanine aminotransferase level was elevated at 700 IU/L. The HCV-RNA titer was still undetectable and the involvement of other possible viruses was negligible. A liver biopsy performed on day 60 showed an acute hepatitis pattern. The discontinuation of therapy alone successfully improved his liver damage on day 84. No other treatments such as steroids were required. According to the diagnostic criteria for drug-induced liver injury in Japan (DDW-J2004), the liver injury observed in this case can be associated with the administration of simeprevir plus pegylated interferon/ribavirin therapy. In conclusion, simeprevir plus pegylated interferon/ribavirin should be used with caution, as these agents may cause unreported serious adverse events including severe liver injury, despite their clinical safety profile.     

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.