The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target

Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals which produce sphingomyelin (SM), several pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. This process is catalyzed by the enzyme IPC synthase, a recognized target for anti-fungals encoded by the AUR1 gene in yeast. Recently, functional orthologues of the AUR1p have been identified in a group of insect vector-borne pathogenic protozoa, the Kinetoplastida, which are responsible for a range of so-called neglected diseases. Of these the Trypanosoma brucei species are the causative agents of human African trypanosomiasis in many of the most under-developed regions of Africa. The available treatments for these diseases are limited, of decreasing efficacy, and often demonstrate severe side-effects. Against this background the T. brucei sphingolipid synthase, an orthologue of the yeast AUR1p, may represent a promising target for novel anti-protozoals. Our studies identify an isoform of this protein as a novel bi-functional enzyme capable of catalyzing the synthesis of both IPC and SM, both known to be present in the parasite. Furthermore, the synthase is essential for parasite growth and can be inhibited by a known anti-fungal at low nanomolar levels in vitro. Most notably this drug demonstrates trypanocidal activity against cultured bloodstream form parasites. Thus, the T. brucei sphingolipid synthase represents a valid and promising drug target.     

Specific congenital malformations after exposure to cyclophosphamide, epirubicin and 5-fluorouracil during the first trimester of pregnancy

Minimal deviation adenocarcinoma (MDA) is a very rare variant of cervical adenocarcinoma, this pathological entity is composed of mucinous very-well-differentiated glands deeply invading cervical stroma, and often surrounded by a desmoplastic reaction. Despite its benign histological appearance, MDA is typically characterized by aggressive clinical behavior and by relevant difficulties in achieving a final diagnosis. Moreover, the intrinsic chemotherapy resistance, as well as the frequent failure of radiotherapy approaches has raised the need to investigate the efficacy of multimodal strategies for the treatment of MDA patients. Here, we report a case of locally advanced MDA of the uterine cervix in a very young woman, who was successfully treated with concomitant chemoradiation followed by radical surgery.     

A case report of fatal tumor lysis syndrome after chemotherapy in a pregnant patient with Burkitt's lymphoma

A 35-year-old Japanese woman in the 24th week of gestation with bilateral breast enlargement was referred to hospital. She was diagnosed with Burkitt's lymphoma and admitted for detailed evaluation and treatment. Early delivery and subsequent chemotherapy was chosen after considering the gestational week, her general condition and the wishes of the patient and her husband. She gave birth to a male infant by cesarean section in the 25(th) week of gestation. It had been planned to begin high-dose chemotherapy, such as CODOX-M/IVAC, on day 7 of the puerperium; however, her general condition worsened and chemotherapy was therefore begun on day 2 after the birth. Eight hours after chemotherapy (cyclophosphamide, vincristine and doxorubicin), she developed cardiac arrest due to tumor lysis syndrome. Despite medical treatment, her bleeding tendency did not improve and she died of respiratory failure with alveolar bleeding five days after chemotherapy.     

Trends in the Leading Causes of Death in Korea, 1983-2012

This study aimed to analyze trends in the 10 leading causes of death in Korea from 1983 to 2012. Death rates were derived from the Korean Statistics Information Service database and age-adjusted to the 2010 population. Joinpoint regression analysis was used to identify the points when statistically significant changes occurred in the trends. Between 1983 and 2012, the age-standardized death rate (ASR) from all causes decreased by 61.6% for men and 51.2% for women. ASRs from malignant neoplasms, diabetes mellitus, and transport accidents increased initially before decreasing. ASRs from hypertensive diseases, heart diseases, cerebrovascular diseases and diseases of the liver showed favorable trends (ASR % change: -94.4%, -53.8%, -76.0%, and -78.9% for men, and -77.1%, -36.5%, -67.8%, and -79.9% for women, respectively). ASRs from pneumonia decreased until the mid-1990s and thereafter increased. ASRs from intentional self-harm increased persistently since around 1990 (ASR % change: 122.0% for men and 217.4% for women). In conclusion, death rates from all causes in Korea decreased significantly in the last three decades except in the late 1990s. Despite the great strides made in the overall mortality, temporal trends varied widely by cause. Mortality trends for malignant neoplasms, diabetes mellitus, pneumonia and intentional self-harm were unfavorable.

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Paclitaxel-eluting nanofiber-covered self-expanding nonvascular stent for palliative chemotherapy of gastrointestinal cancer and its related stenosis

Self-expanding non-vascular metal stents (SEMS) is now a choice of treatment for tumor-induced obstructive symptoms of gastrointestinal tract. But in-growing tumor causes re-stenosis. Here, we studied a paclitaxel-eluting nanofiber-covered stent for palliative chemotherapy of gastrointestinal cancer and its related stenosis. In vivo and in vitro feasibility of nanofiber-covered nonvascular stent was evaluated in this study. Nanofiber-covered stent released paclitaxel (PTX) in controlled manner for 30 days. PTX-NFM significantly inhibited the growth of CT-26 colon cancer in comparison with PTX injection. PTX maintained higher tumor concentrations over 1.0 μg/ml for more than 14 days without systemic exposure. TUNEL and H&E staining proved locally concentrated PTX induced the higher apoptosis than PTX injection. In this way, PTX-eluting nanofiber-covered stent possibly inhibits in-growth of cancer and extends patency of stent. Clinical feasibility of PTX-eluting nanofiber nonvascular stent for cholangiocarcinoma and gastrointestinal cancers will be investigated in further studies.     

Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study

IntroductionPriapism is the persistent and painful erection of the penis and is a common sickle cell disease (SCD) complication.AimThe goal of this study was to characterize clinical and genetic factors associated with priapism within a large multi-center SCD cohort in Brazil.MethodsCases with priapism were compared to SCD type-matched controls within defined age strata to identify clinical outcomes associated with priapism. Whole blood single nucleotide polymorphism genotyping was performed using a customized array, and a genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms associated with priapism.Main Outcome MeasureOf the 1,314 male patients in the cohort, 188 experienced priapism (14.3%).ResultsPriapism was more common among older patients (P = .006) and more severe SCD genotypes such as homozygous SS (P < .0001). In the genotype- and age-matched analyses, associations with priapism were found for pulmonary hypertension (P = .05) and avascular necrosis (P = .01). The GWAS suggested replication of a previously reported candidate gene association of priapism for the gene transforming growth factor beta receptor 3 (TGFBR3) (P = 2 × 10^?4).Clinical ImplicationsOlder patients with more severe genotypes are at higher risk of priapism, and there is a lack of consensus on standard treatment strategies for priapism in SCD.Strengths & LimitationsThis study characterizes SCD patients with any history of priapism from a large multi-center cohort. Replication of the GWAS in an independent cohort is required to validate the results.ConclusionThese findings extend the understanding of risk factors associated with priapism in SCD and identify genetic markers to be investigated in future studies to further elucidate priapism pathophysiology.Ozahata M, Page GP, Guo Y, et al. Clinical and Genetic Predictors of Priapism in Sickle Cell Disease: Results from the Recipient Epidemiology and Donor Evaluation Study III Brazil Cohort Study. J Sex Med 2019;16:1988–1999.     

口腔黏膜游离移植尿道再造术患者的围术期护理

对8例尿道缺损患者行口腔黏膜游离移植尿道再造术,8例患者一期术后移植黏膜均存活,无皮片坏死、感染等并发症,术后1个月、3个月复查见移植黏膜存活良好;术后6个月来院行二期手术,术后拔出导尿管,小便通畅,未见尿漏、感染、移植黏膜坏死等并发症。术后回访3～18个月,尿道通畅,无分叉及狭窄。提出术前加强心理护理、口腔护理、会阴部准备;术后注意饮食护理、排便的护理;密切观察口腔伤口并加强口腔护理,做好会阴护理、并发症治疗及出院指导,可保证治疗效果,提高患者术后生活质量。