Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels for the improvement of clinical outcomes in patients with renal dysfunction

We evaluated the clinical efficacy and safety of teicoplanin according to the pharmacokinetics (PK) therapeutic level achieved in patients with renal dysfunction. Target trough concentration (C_min) was ≥15–30 μg/ml which has been recommended in patients with normal renal function. Adult patients (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m²) who were treated by teicoplanin were included in the study. We adopted two types of regimen for the initial 3 days: the conventional regimen, and the enhanced loading regimen (10 mg/kg twice daily on the 1st day, followed by 6.7–10 mg/kg once daily for the 2nd and 3rd days]. Two hundred and eighty-eight patients were evaluated for safety, and 106 patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were evaluated for clinical efficacy. A significantly higher success rate was obtained in patients who achieved the target initial C_min compared with those that did not (75.0 % vs 50.0 %, p?=?0.008). In a multivariate analysis, initial C_min ≥15 μg/ml was an independent factor for clinical success (adjusted odds ratio: 4.20, 95 % confidence interval: 1.34–13.15). In patients with 15–30 μg/ml of maximal C_min during therapy, nephrotoxicity occurred in 13.1 %, and hepatotoxicity in 2.6 %, and these incidences were not significantly higher compared with those patients with <15 μg/ml. In conclusion, achievement of C_min of 15–30 μg/ml without delay was necessary to improve clinical outcomes for the treatment by teicoplanin in patients with renal dysfunction. Further investigation is required regarding the optimal loading regimen to achieve the therapeutic levels in those patients.     

Glomerular cytokine expression in murine lupus nephritis

Background

Aberrant expression of T helper cell (Th) cytokines is believed to play a central role in the pathogenesis of systemic lupus erythematosus (SLE). While the glomerulus is one of the major targets of lupus inflammation, little is known about the cytokine expression in glomeruli. The current study aimed to explore the profiles of Th cytokine gene expressions in isolated glomeruli of lupus-prone mice.

Methods

Glomeruli were purified from lupus-prone MRL/lpr mice using the magnetic microbead method. Expressions of cytokine genes representing the Th subset and FoxP3 were examined using real-time polymerase chain reaction. Serum levels of these cytokines were also measured by enzyme-linked immunosorbent assay. MRL/n mice were used as controls. Histologic glomerular damages were scored semiquantitatively. To examine the role of TNF-α in glomerular damage, we administered etanercept, a TNF-α antagonist, into the subjects.

Results

Glomerular gene expressions of TNF-α in lpr mice increased with week postpartum and reached statistically significant levels at 16 weeks compared with those of the glomeruli from control mice. Expressions of IFN-γ, IL-4 and FoxP3 also increased, but the difference was not significant. There was a significant increase in serum levels of TNF-α, IFN-γ, and IL-17 and decrease in those of IL-4. Among the genes examined, TNF-α significantly correlated with glomerular damage score. Administration of etanercept did not affect glomerular cytokine expressions or proteinuria and failed to ameliorate histologic glomerular damages.

Conclusion

Our data suggest that Th1 cytokines, especially TNF-α, are dominantly expressed in the glomeruli of lupus-prone mice, but its pathophysiological role remains unclear.

     

Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.     

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood,adolescent, and young adult cancer patients: part 1

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

     

Expression of TrkB and BDNF is associated with poor prognosis in non-small cell lung cancer

High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P=0.010) and BDNF (P=0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P=0.0094) and overall survival (P=0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95%C.I. 1.560-11.068, P=0.002) and overall survival (HR 4.335, 95%C.I. 1.534-15.963, P=0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients.     

Reoperation for recurrent lumbar disc herniation: a study over a 20-year period in a Japanese population

BackgroundMany studies have been reported on recurrent lumbar disc herniations covering several pathological conditions. In those studies, reoperation rate of revised disc excisions was calculated by simple division between the number of reoperations and that of the total primary disc excisions. To determine the real reoperation rate, strict definition of pathologies, a large number of patients, a long observation period, and survival function method are necessary.MethodsBetween 1988 and 2007, 5,626 patients with disc excision were enrolled by the spine registration system of the Department of Orthopaedic Surgery, Tohoku University, Japan. Among them, 192 had revised disc surgery, and we obtained data of 186 patients whose clinical features were assessed and reoperation rates analyzed using the Kaplan–Meier method.ResultsIn total, 205 disc herniations were excised in the revision surgery (including contralateral herniation at the same level and new herniation at a different level), and 101 were real recurrent herniations (recurrence at the same level and side as the primary herniation). The kappa coefficient of the spinal level and side between the primary and revision surgeries was 0.41, indicting moderate correlations. Real recurrent herniations showed shorter intervals between primary and revision surgeries. Male patients with surgery at a younger age carried a higher risk of reoperation. In the revision surgery, transligamentous extrusion was significantly more common than other types of herniation. On Kaplan–Meier analysis, the reoperation rate of overall revised excisions was 0.62% at 1 year, 2.4% at 5 years, 4.4% at 10 years, and 5.9% after 17 years. That of real recurrent herniations was 0.5%, 1.4%, and 2.1%, respectively, and 2.8% after 15.7 years.ConclusionReoperation rate of real recurrent herniations calculated using survival function method gradually increased year by year, from 0.5% at 1 year after primary surgery to 2.8% at 15.7 years.     

Pregnancy outcomes in patients with systemic lupus erythematosus with or without a history of lupus nephritis

Clinical and Experimental Nephrology - Pregnancy is an important issue for many women with systemic lupus erythematosus (SLE). This study examined maternal and fetal outcomes among SLE women with...     

Three year longitudinal study for out-of-hospital cardiac arrest in Osaka Prefecture

OBJECTIVE: To analyze the longitudinal changes in the treatment of out-of-hospital cardiac arrests. These analyses have focused on the time interval from the receipt of call until defibrillation of patients with ventricular fibrillation. DESIGN: Population-based, prospective longitudinal study according to the Utstein style. Setting: Osaka Prefecture (population 8, 800, 000), served by 36 municipal fire and emergency departments. PATIENTS: Consecutive, out-of-hospital cardiac arrests occurring between May 1998 and April 2001. MAIN OUTCOME MEASURES: Change in the interval to defibrillation, and one-year survival from cardiac arrest. RESULTS: Of the 15,211 cases of confirmed cardiac arrests during the three years, resuscitation was attempted in 14,609 subjects. Of the 2957 cases of cardiac origin and witnessed by bystanders, 90 cases (3.0%) were alive 1 year following the episode. In 383 cases of defibrillation, the interval from receipt of call to defibrillation was evaluated annually. This interval decreased significantly during the three year course (14.5, 13.0, and 11.5 min expressed by the median), suggesting that this project to report the data of out-of-hospital arrests was an effective campaign for EMT. However, the outcome did not improve significantly during this period (3.0%, 2.6%, and 3.6% alive 1 year in witnessed arrests with cardiac etiology). This may be because the third year median duration of 11.5 min, is still insufficient to indicate a significant improvement in the outcome. CONCLUSIONS: This project to report the data of out-of-hospital cardiac arrest might have contributed to the reduction of the interval for defibrillation, as a campaign for the EMTs; although the decrease in this interval was still insufficient to result in a significant increase in the number of cases who are alive one year later.