Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC_48–72) that were <50% of the SAB-IE AUC_48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC_48–72 values, while maintaining acceptable trough concentration (C_min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C_min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C_min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.     

Validity and reliability of wheelchair sitting posture measures using Coach’s Eye in abled subjects

People in wheelchairs spend a long time in the sitting position and often incur alignment problems resulting in neck and back pain. This study: (1) assessed the validity/reliability of Coach’s Eye (CE) smart device application, (2) examined the effect of seat to back support angle adjustments on head, neck, and shoulder posture in the sitting position, and (3) compared changes in cervical rotation at each back support angle. Abled subjects sat in a wheelchair with back support angles positioned at 90°, 100°, and 110°. CE, as well as ImageJ software, was used to analyze three angles: sagittal head angle (SHA), cervical angle (CVA), and shoulder angle (SA). There were highly significant differences for CVA and SA (p < 0.001) among the three seat to back support angles. Validity of CE was examined by correlating CE with ImageJ scores. CE had high validity for all angles (r = 0.99, 0.98, 0.99 respectively, p < 0.001). Inter-rater reliability for SHA, CVA, and SA was high (intraclass correlation coefficient [ICC] ranged from 0.95 to 0.99). Head (CVA) and shoulder (SA) alignment was closest to neutral posture with back support angles set at 110° and 90°, respectively.     

Potential role of acid ceramidase in conversion of cytostatic to cytotoxic end-point in pancreatic cancer cells

Purpose

Acid ceramidase (AC) occupies an important place in the control of cancer cell proliferation. We tested the influence of AC inhibition on the effects of PSC 833, a P-glycoprotein antagonist with potent ceramide-generating capacity, to determine whether AC could be a therapeutic target in pancreatic cancer.

Methods

Ceramide metabolism was followed using ³H-palmitate, and molecular species were determined by mass spectroscopy. Apoptosis was measured by DNA fragmentation, autophagy by acridine orange staining, and cell cycle was assessed by flow cytometry and RB phosphorylation. AC was measured in intact cells using fluorescent substrate.

Results

Exposure of human PANC-1 or MIA-PaCa-2 cells to PSC 833 promoted increases in de novo (dihydro)ceramides, (dihydro)glucosylceramides, and (dihydro)sphingomyelins, demarking ceramide generation and robust metabolism. Despite the multifold increases in (dihydro)ceramide levels, cells were refractory to PSC 833. However, PSC 833 produced a dose-dependent decrease in DNA synthesis and dose- and time-dependent decreases in RB phosphorylation, consistent with cell cycle arrest as demonstrated at G1. Cytostatic effects of PSC 833 were converted to cytotoxic end-point by acid ceramidase inhibition. Cytotoxicity was accompanied by formation of acridine orange-stained acidic vesicles and an increase in LC3 expression, indicative of autophagic response. Cell death was not reversed by preexposure to myriocin, which blocks PSC 833-induced ceramide generation.

Conclusion

Although the role of ceramide in end-point cytotoxicity is unclear, our results suggest that acid ceramidase is a viable target in pancreatic cancer. We propose that AC inhibition will be effective in concert with other anticancer therapies.     

Tracking cell invasion of human glioma cells and suppression by anti-matrix metalloproteinase agent in rodent brain-slice model

Persistent expression of green fluorescent protein (GFP) in human malignant glioma cell clones (U87MG, U251MG, and U373MG) was established using the pEGFP-C1 vector. Tumor spheroid was implanted into the caudate nucleus-putamen of a severely compromised immunodeficient (SCID) mouse brain slice. To allow quantitative assessment of tumor cell invasion, the invasion area index was measured on days 1, 3, 5, and 7 by a fluorescence stereomicroscope and an image analyzer in the presence of varying concentrations of SI-27. In the control group (0μg/ml), all glioma cell lines invaded in a fingerlike fashion, reaching the contralateral hemisphere via the corpus callosum. SI-27 at concentrations of 10, 50, or 100 μg/ml significantly suppressed the index on days 5 and 7 in a dose-dependent manner, whereas 1 μg/ml had no effect. Laser confocal microscopy indicated that the tumor cells penetrated through the brain slice. This model enabled unequivocal periodic tracking of individual invading tumor cells in the normal brain. The significant suppression of glioma cell invasion by SI-27 indicates that anti-matrix metalloproteinase (MMP) treatment may represent an important future therapeutic strategy for malignant cerebral neoplasms.     

Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma

Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear β-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup.     

The value of magnetic resonance sialography and magnetic resonance imaging versus conventional sialography of the parotid gland in the diagnosis and staging of Sjögren’s syndrome

Introduction

The conventional sialography (CS) and minor salivary gland biopsy have been considered the cornerstones of the diagnosis of Sjögren’s syndrome (SS). However, they are invasive and with risk of complications to the patient. Magnetic resonance imaging (MRI) has been widely replacing conventional invasive examinations. They provide insufficient data for diagnosing and staging SS, because while they address the detection and diagnosis of parenchymal salivary gland disease they do not assess duct abnormalities. The introduction of magnetic resonance sialography (MRS) protocol was the first step towards non-ionizing non-invasive technique enables a more accurate assessment of the duct system. Moreover, it is postulated that the combined use of MRI and MRS is useful for the assessment of damaged salivary glands in SS.

Aim of work

This preliminary study aimed to assess the role and efficacy of MRS and MRI in imaging the parotid gland in SS patients’ and to compare their results with that of CS in the diagnosis and staging of SS.

Patients and methods

The parotid gland was examined by MRS, MRI and CS in 15 SS patients. Scoring system for overall branching pattern, ductal system staging, sialectasis for both CS and MRS was used. MRI scoring system for glandular parenchymal pattern, size and contour and lymph node was used.

Results

This revealed non-significant difference between CS and MRS findings in the diagnosis and staging of SS. Furthermore, no statistically significant correlation was found between the clinical and SS stage in both CS and MRS. On the other hand, a statistically significant positive correlation was found between the clinical findings and the MRI parenchymal stages. Moreover, MRS showed higher sensitivity and diagnostic accuracy values than CS. Combining the MRS and MRI abnormalities, 100% sensitivity diagnostic accuracy values were achieved in the diagnosis and staging of SS. The inter-observer agreement was higher in MRS than in CS and was perfect in MRI.

Conclusion

In this preliminary study, MRS showed a higher sensitivity and accuracy in diagnosing and staging SS and may safely and securely replace CS. MRI and MRS give information on different aspects of glandular and duct pathology; therefore, both should be performed when examining the parotid glands in SS patients.     

Mycobacterium tuberculosis infection in systemic lupus erythematosus patients

Aim of the work

To estimate prevalence of tuberculosis (TB) infection in systemic lupus erythematosus (SLE) patients; to study its relation to disease duration, activity, damage and treatment as well as to compare the performance of interferon gamma (IFN-γ) release assay and tuberculin skin test (TST) in detection of TB infection.

Methotrexate versus cyclosporine in the treatment of severe atopic dermatitis in children: a multicenter experience from Egypt

Topical therapy is usually of limited benefit in the treatment of severe atopic dermatitis (AD), and the need for a safe and effective systemic treatment may be required in certain cases especially in children. We evaluated the efficacy and safety of methotrexate and cyclosporine in the treatment of 40 children with severe AD. Patients were divided into two groups (each consisting of 20 patients); group A was treated with methotrexate (7.5 mg/week) while group B was treated with cyclosporine (2.5 mg/kg/day). The severity scoring for atopic dermatitis (SCORAD) was used to indicate efficacy of treatment. In group A, the mean SCORAD score at the beginning of the study was 57.90?±?3.21 that was reduced at the end of the treatment period to reach 29.35?±?6.32 with a mean absolute reduction of 26.25?±?7.03. In group B, the mean SCORAD score was 56.54?±?4.82 at the start of treatment and was 31.35?±?8.89 at the end of 12 weeks of treatment. The mean absolute reduction was 25.02?±?8.21. There was no statistically significant difference in the reduction of SCORAD score between both groups (P?±?0.93). Mild and temporary adverse effects were reported in some patients in both groups. Conclusion: Methotrexate or cyclosporine in low doses can be considered as effective, relatively safe, and well-tolerated treatments for severe AD in children.