Characterization of the depsidone gene cluster reveals etherification, decarboxylation and multiple halogenations as tailoring steps in depsidone assembly

Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural diversity. Previous structure‒activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic activity. However, the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin ( 3) remain enigmatic. In this study, we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption, heterologous expression and in vitro biochemical experiments. We demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and non-reducing polyketide synthase, which is distinct from the common depside skeleton biosynthesis. This skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation, respectively. In addition, the decarboxylase DepF exhibited substrate promiscuity for different scaffold substrates. Finally, and interestingly, we discovered a halogenase encoded remotely from the biosynthetic gene cluster, which catalyzes triple-halogenation to produce the active end product nornidulin ( 3). These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.

Extensive expansion of the chemical diversity of fusidane-type antibiotics using a stochastic combinational strategy

Fusidane-type antibiotics, represented by helvolic acid, fusidic acid and cephalosporin P

Research Progress of Adaptive Intervention / 中国医学科学院学报

Adaptive intervention(AI)is a methodology which dynamically evaluates adaptive variables at decision points and timely adjusts and develops tailored strategies to meet individual needs.The study reviewed the origin and development and elaborated the core elements(including intervention outcomes,intervention options,decision points,tailoring variables,and decision rules)and the classification of AI.Based on the literature,the key points of the design and implementation of AI were prospected,which can provide evidence for the research and development of health behavior intervention.

Personalized approach to growth hormone replacement in adults

ABSTRACT Growth hormone (GH) deficiency (GHD) in adults is well-characterized and includes abnormal body composition, reduced bone mass, an adverse cardiovascular risk profile, and impaired quality of life. In the early 1990s, it was also shown that patients with hypopituitarism without GH replacement therapy (GHRT) had excess mortality. Today, GHRT has been shown to decrease or reverse the negative effects of GHD. In addition, recent papers have shown that mortality and morbidity are approaching normal in hypopituitary patients with GHD who receive modern endocrine therapy including GHRT. Since the first dose-finding studies, it has been clear that efficacy and side effects differ substantially between patients. Many factors have been suggested as affecting responsiveness, such as sex, age, age at GHD onset, adherence, and GH receptor polymorphisms, with sex and sex steroid replacement having the greatest impact. Therefore, the individual tailoring of GH dose is of great importance to achieve sufficient efficacy without side effects. One group that stands out is women receiving oral estrogen replacement, who needs the highest dose. Serum insulin-like growth factor-1 (IGF-1) is still the most used biochemical biomarker for GH dose titration, although the best serum IGF-1 target is still debated. Patients with GHD due to acromegaly, Cushing's disease, or craniopharyngioma experience similar effects from GHRT as others. Arch Endocrinol Metab. 2019;63(6):592-600

Tailoring radicality in early cervical cancer: how far can we go? / 부인종양

Today, the patient who is diagnosed with early cervical cancer is offered a variety of treatments apart from standard therapy. Patients can be treated with a less radical hysterectomy (RH) regarding parametrectomy, a trachelectomy either vaginal or abdominal, and this can be performed through a minimal invasive or open procedure. All this in combination with nerve sparing and/or sentinel node technique. Level 1 evidence for the oncological safety of all these modifications is only available from 3 randomized controlled trials (RCTs). Two RCTs on more or less radical parametrectomy both showed that oncological safety was not compromised by doing less radical surgery. Because of the heterogeneity of the patient population and the high frequency of adjuvant radiotherapy, the true impact of surgical radicality cannot be assessed. Regarding the issue of oncological safety of fertility sparing treatments, case-control and retrospective case series suggest that trachelectomy is safe as long as the tumor diameter does not exceed 2 cm. Recently, both a RCT and 2 case-control studies showed a survival benefit for open surgery compared to minimally invasive surgery, whereas many previous case-control and retrospective case series on this subject did not show impaired oncological safety. In a case-control study the survival benefit for open surgery was restricted to the group of patients with a tumor diameter more than 2 cm. Although modifications of the traditional open RH seem safe for tumors with a diameter less than 2 cm, ongoing prospective RCTs and observational studies should give the final answer.

Good clinical practice guide for opioids in pain management: the three Ts - titration (trial), tweaking (tailoring), transition (tapering) / Orientação para boa prática clínica para opioides no tratamento da dor: os três "Ts" - titulação (teste), ajustes (individualização), transição (redução gradual)

ABSTRACT BACKGROUND AND OBJECTIVES: Achieving good clinical practice in the use of opioids as part of a comprehensive pain management regimen can face significant challenges. Despite guidelines from governmental and pain society/organization sources, there are still significant hurdles. A review of some basic tenets of opioid analgesia based on current published knowledge and experiences about this important healthcare imperative is warranted. CONTENT: Consistent with guidelines, the literature supports using the lowest total opioid dose that provides adequate pain control with the fewest adverse effects. Titration (or trial) during opioid initiation is a way of starting low and going slow (and assessing the appropriateness of a specific opioid and formulation). Recognizing that multiple factors contribute to an individual's personal experience of pain, the physical, psychological, social, cultural, spiritual, pharmacogenomic, and behavioral factors of the individual patient should be taken into account (tweaking, or tailoring). Finally, for those patients for whom transition (tapering) from opioid is desired, doing so too rapidly can have negative consequences and minimization of problems during this step can be achieved by proper tapering. CONCLUSION: We conclude that a simultaneously aggressive, yet conservative, approach is advocated in the literature in which opioid therapy is divided into three key steps (the 3 T's): titration (or trial), tweaking (or tailoring), and transition (or tapering). Establishment of the 3 T's along with the application of other appropriate good medical practice and clinical experience/judgment, including non-pharmacologic approaches, can assist healthcare providers in the effort to achieve optimal management of pain.

RESUMO JUSTIFICATIVA E OBJETIVOS: Uma boa prática clínica com o uso de opioides como parte de um regime abrangente de tratamento da dor pode enfrentar desafios significativos. Apesar das diretrizes provenientes de sociedades/organizações não governamentais para o manejo da dor, ainda existem obstáculos significativos. A revisão de alguns princípios básicos da analgesia com opioide com base na experiência e no conhecimento das publicações atuais sobre esse cuidado importante da saúde é justificável. CONTEÚDO: De acordo com as diretrizes, a literatura apoia o uso da dose total mais baixa de opioides que forneça o controle adequado da dor com menos efeitos adversos. A titulação (teste), ao iniciar a administração de um opioide, é uma maneira de começar com uma concentração baixa e ir devagar (avaliar a adequação da fórmula específica de um opioide). O ajuste (individualização) é reconhecer que vários fatores contribuem para a experiência pessoal da dor de um indivíduo, tais como fatores físicos, psicológicos, sociais, culturais, espirituais, farmacogenômicos e comportamentais. Finalmente, para aqueles pacientes nos quais a transição (redução gradual) do opioide é desejada, fazer essa transição muito rapidamente pode ter consequências negativas e é possível minimizar os problemas durante essa etapa por meio de uma redução gradual. CONCLUSÃO: Uma abordagem simultânea, agressiva, porém conservadora, é defendida na literatura em que a terapia com opioides é dividida em três etapas principais (os 3 Ts - em inglês: titration, tailoring, tapering): titulação (teste), ajuste (individualização) e transição (redução gradual). Estabelecer os três Ts, juntamente com a aplicação de outra boa prática médica e experiência/julgamento clínico, incluindo abordagens não farmacológicas, pode ajudar os profissionais de saúde no esforço para alcançar o tratamento ideal da dor.

Cost Effectiveness of Interventions to Promote Screening for Colorectal Cancer: A Randomized Trial / 예방의학회지

OBJECTIVES: Screening for colorectal cancer is considered cost effective, but is underutilized in the U.S. Information on the efficiency of "tailored interventions" to promote colorectal cancer screening in primary care settings is limited. The paper reports the results of a cost effectiveness analysis that compared a survey-only control group to a Centers for Disease Control (CDC) web-based intervention (screen for life) and to a tailored interactive computer-based intervention. METHODS: A randomized controlled trial of people 50 and over, was conducted to test the interventions. The sample was 1224 partcipants 50-70 years of age, recruited from Kelsey-Seybold Clinic, a large multi-specialty clinic in Houston, Texas. Screening status was obtained by medical chart review after a 12-month follow-up period. An "intention to treat" analysis and micro costing from the patient and provider perspectives were used to estimate the costs and effects. Analysis of statistical uncertainty was conducted using nonparametric bootstrapping. RESULTS: The estimated cost of implementing the web-based intervention was $40 per person and the cost of the tailored intervention was $45 per person. The additional cost per person screened for the web-based intervention compared to no intervention was $2602 and the tailored intervention was no more effective than the web-based strategy. CONCLUSIONS: The tailored intervention was less cost-effective than the web-based intervention for colorectal cancer screening promotion. The web-based intervention was less cost-effective than previous studies of in-reach colorectal cancer screening promotion. Researchers need to continue developing and evaluating the effectiveness and cost-effectiveness of interventions to increase colorectal cancer screening.

Computational Approach for the Analysis of Post-PKS Glycosylation Step

We introduce a computational approach for analysis of glycosylation in Post-PKS tailoring steps. It is a computational method to predict the deoxysugar biosynthesis unit pathway and the substrate specificity of glycosyltransferases involved in the glycosylation of polyketides. In this work, a directed and weighted graph is introduced to represent and predict the deoxysugar biosynthesis unit pathway. In addition, a homology based gene clustering method is used to predict the substrate specificity of glycosyltransferases. It is useful for the rational design of polyketide natural products, which leads to in silico drug discovery.

Computational Approach for Biosynthetic Engineering of Post-PKS Tailoring Enzymes

Compounds of polyketide origin possess a wealth of pharmacological effects, including antibacterial, antifungal, antiparasitic, anticancer and immunosuppressive activities. Many of these compounds and their semisynthetic derivatives are used today in the clinic. Most of the gene clusters encoding commercially important drugs have also been cloned and sequenced and their biosynthetic mechanisms studied in great detail. The area of biosynthetic engineering of the enzymes involved in polyketide biosynthesis has recently advanced and been transferred into the industrial arena. In this work, we introduce a computational system to provide the user with a wealth of information that can be utilized for biosynthetic engineering of enzymes involved in post-PKS tailoring steps. Post-PKS tailoring steps are necessary to add functional groups essential for the biological activity and are therefore important in polyketide biosynthesis.

A Case of Successful Repair with Aortic Tailoring for Chronic Type B Aortic Dissection / 日本心臓血管外科学会雑誌

A 64-year-old woman with dyspnea on exertion was referred to our hospital. CT revealed type B aortic dissection with 7cm of aneurysm including a thrombus in the false lumen at the distal aortic arch. Four intimal tears at the distal aortic arch were closed directly during hypothermic circulatory arrest, and the descending thoracic aorta was tailored without a prosthetic graft after fixation of the dissecting adventitia to the intima at the distal portion of the false lumen. The postoperative course was uneventful and this patient was discharged on the 22nd postoperative day. Three years after surgery, the postoperative CT revealed no evidence of dilatation of the descending thoracic aorta as far as the abdominal aorta although the dissection of thoracoabdominal aorta remained. This technique is effective as an surgical option for chronic type B aortic dissection to minimize operative stress and complications.

Brain Surgery for Epilepsy under Propofol I.V. Anesthesia / 대한마취과학회지

The treatment for epilepsy has been studied throughout the course of human history. However, radical treatment of epilepsy has only been discovered recently with introduction of surgical treatment until now, palliative drug administration was common practice. During the anesthetic procedure for epilepsy surgery it is necessary for the patient to be alert and to cooperate with the surgeon while mapping and subcutaneous EEG test are carried out during the surgery. For this type of procedure, a new I.V. anesthetic, propofol is considered to be an ideal anesthetic agent because propofol is a short-acting and clear headed I.V. anesthetic agent for induction as the well as the maintenance of genenral anesthesia. In this study, only propofol was administered intravenously in 20 randomiied patients scheduled for brain surgery for epilepsy treatment. The mean infusion rate was 100 mcg/kg/min to maintain a satisfactory anesthesia. For the induction of anesthesia, slightly higher doses were required. The cardiovascular effects of propofol infusion was associated with slightly decrease of systolic, diastolic and mean arterial pressures. Arterial blood gases were analyzed for the evaluation of ventilatory function. PaCO2 were 41+/-4.23 mmHg preoperatively, 44+/-5.28 mmHg 30 min. following sedation, 42+/-6.35 mmHg 30 min. following awakening, 46+/-6.37 mmHg 30 min. following resedation, 44+/-4.79 mmHg at 2 hours and 44+/-6.51 mmHg at 4 hours after resedation and 36+/-3.98 mmHg 30 min. following recovery. PaO2 were 101+/-31.3 mmHg preoperatively, 190+/-47.13 mmHg 30 min. following sedation, 195+/-32 mmHg 30 min. following awakening, 209+/-29.23 mmHg 30 min. and 210+/-34.55 mmHg at 2 hours and 190+/-37.36 mmHg 4 hours following resedation, and 10.2+/-31.36 mmHg 30 min. following. PH were 7.38 preoperatively, 7.34+/-0.04 following sedation, 7.34+/-0.03 30 min. following awakening, 7.34+/-0.03 at 30 min. following resedation, 7.35+/-0.03 at 2 hours and 7.36+/-0.03 at 4 hours following resedation, and 7.38+/-3.98 at 30 min. after recovery. The duration of anesthesia was 8.5-12 hours. The duration of propofol anesthesia ranged from 8 to 9 hours. The awakening time from the cessation of propofol infusion ranged from 3 to 17 minutes. As the result of this study, we came to the conclusion that propofol is an ideal intravenous anesthetic for brain surgery for epilepsy treatment.

Brain Surgery for Epilepsy under Propofol I.V. Anesthesia / 대한마취과학회지

The treatment for epilepsy has been studied throughout the course of human history. However, radical treatment of epilepsy has only been discovered recently with introduction of surgical treatment until now, palliative drug administration was common practice. During the anesthetic procedure for epilepsy surgery it is necessary for the patient to be alert and to cooperate with the surgeon while mapping and subcutaneous EEG test are carried out during the surgery. For this type of procedure, a new I.V. anesthetic, propofol is considered to be an ideal anesthetic agent because propofol is a short-acting and clear headed I.V. anesthetic agent for induction as the well as the maintenance of genenral anesthesia. In this study, only propofol was administered intravenously in 20 randomiied patients scheduled for brain surgery for epilepsy treatment. The mean infusion rate was 100 mcg/kg/min to maintain a satisfactory anesthesia. For the induction of anesthesia, slightly higher doses were required. The cardiovascular effects of propofol infusion was associated with slightly decrease of systolic, diastolic and mean arterial pressures. Arterial blood gases were analyzed for the evaluation of ventilatory function. PaCO2 were 41+/-4.23 mmHg preoperatively, 44+/-5.28 mmHg 30 min. following sedation, 42+/-6.35 mmHg 30 min. following awakening, 46+/-6.37 mmHg 30 min. following resedation, 44+/-4.79 mmHg at 2 hours and 44+/-6.51 mmHg at 4 hours after resedation and 36+/-3.98 mmHg 30 min. following recovery. PaO2 were 101+/-31.3 mmHg preoperatively, 190+/-47.13 mmHg 30 min. following sedation, 195+/-32 mmHg 30 min. following awakening, 209+/-29.23 mmHg 30 min. and 210+/-34.55 mmHg at 2 hours and 190+/-37.36 mmHg 4 hours following resedation, and 10.2+/-31.36 mmHg 30 min. following. PH were 7.38 preoperatively, 7.34+/-0.04 following sedation, 7.34+/-0.03 30 min. following awakening, 7.34+/-0.03 at 30 min. following resedation, 7.35+/-0.03 at 2 hours and 7.36+/-0.03 at 4 hours following resedation, and 7.38+/-3.98 at 30 min. after recovery. The duration of anesthesia was 8.5-12 hours. The duration of propofol anesthesia ranged from 8 to 9 hours. The awakening time from the cessation of propofol infusion ranged from 3 to 17 minutes. As the result of this study, we came to the conclusion that propofol is an ideal intravenous anesthetic for brain surgery for epilepsy treatment.

Clinical Observation on Ureteral Tailoring in 13 Cases / 대한비뇨기과학회지

A clinical observation was made on 13 cases (15 ureters) who were performed ureteral tailoring at the Department of Urology, Catholic Medical College, from 1968 to 1981. Clinical observation was included age and sex distribution, indication for operation, methods of operation, duration of indwelling ureteral splint catheter and complications. The results were as follows: 1. Ureteral tailoring was performed in the case of severe dilated ureter due to ureteral obstruction, V-U refiuxand/or megaloureter. 2. Most case had undergone antirefiux procedures except 2 cases: 12 ureters of 10 cases underwent antirefiuxprocedure of Politano-Leadbetter technic and the other one was Paquin technic. 3. Mean duration of keeping splint catheter was 11 days. 4. Temporary nephrostomy was performed in 4 cases due to poor renal function. 5. Complications had been observed in 6 cases, which included septicemia, ureteral stricture, uremia, urineleakage and urinary infection.

Ureteral Tailoring and Anti-reflux Procedure in 6 Cases / 대한비뇨기과학회지

A clinical observation on ureteral tailoring with anti-reflux procedure on 6 ureters of 5 patients were reported herein. Four ureters of 3 children were hydroureteronephrosis with vesicoureteral reflux due to bladder neck contracture. Two ureters of housewives were megaloureter. The results of 5 cases were summarized as follows: 1. The length of tailoring was 8 cm. in average. 2. Tailored ureters were approximated by continuous suture plus simple sutures in 2 ureters of 1 case, everting plus simple sutures in 3 cases and the other was by everting sutures alone. No difference in methods of approximation was found in result. 3. All cases had undergone antireflux procedures. Five ureters of 4 cases were done by Politano-Leadbetter technic and the other one by Paquin technic. 4. Mean duration of splinting was some 2 weeks. We believe that splinting is essential for more than 10 days. 5. One case was died of septicemia on 7th postoperative day. Another case shows only unsterile urine yet. Satisfactory results were obtained from remaining 3 cases.