Generation of CD1+RelB+ dendritic cells and tartrate-resistant acid phosphatase-positive osteoclast-like multinucleated giant cells from human monocytes

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) stimulate the differentiation of human monocytes into two phenotypically distinct types of macrophages. However, in vivo, not only CSF but also many other cytokines are produced under various conditions. Those cytokines may modulate the differentiation of monocytes by CSFs. In the present study, we showed that CD14+ adherent human monocytes can differentiate into CD1+relB+ dendritic cells (DC) by the combination of GM-CSF plus interleukin-4 (IL-4) and that they differentiate into tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like multinucleated giant cells (MGC) by the combination of M-CSF plus IL-4. However, the monocyte-derived DC were not terminally differentiated cells; they could still convert to macrophages in response to M-CSF. Tumor necrosis factor-alpha (TNF-alpha) stimulated the terminal differentiation of the DC by downregulating the expression of the M-CSF receptor, cfms mRNA, and aborting the potential to convert to macrophages. In contrast to IL-4, interferon-gamma (IFN-gamma) had no demonstrable effect on the differentiation of monocytes. Rather, IFN- gamma antagonized the effect of IL-4 and suppressed the DC and MGC formation induced by GM-CSF + IL-4 and M-CSF + IL-4, respectively. Taken together, these results provide a new aspect to our knowledge of monocyte differentiation and provide evidence that human monocytes are flexible in their differentiation potential and are precursors not only of macrophages but also of CD1+relB+DC and TRAP-positive MGC. Such a diverse pathway of monocyte differentiation may constitute one of the basic mechanisms of immune regulation.     

The art of gene therapy for glioma： a review of the challenging road to the bedside

Glioblastoma muhiforme （GBM） is a highly invasive brain tumour that is unvaryingly fatal in humans clesplte even aggres- sive therapeutic approaches such as surgical resection followed by chemotherapy and radiotherapy. Unconventional treatment options such as gene therapy provide an intriguing option for curbing glioma related deaths. To date, gene therapy has yielded encouraging results in preclinical animal models as well as promising safety profiles in phase I clinical trials, but has failed to demonstrate significant therapeutic efficacy in phase III clinical trials. The most widely studied antiglioma gene therapy strategies are suicide gene therapy, genetic immuno- therapy and oncolytic virotherapy, and we have attributed the challenging transition of these modalities into the clinic to four major road- blocks ： （ 1 ） anatomical features of the central nervous system, （2） the host immune system, （3） heterogeneity and invasiveness of GBM and （4） limitations in current GBM animal models. In this review, we discuss possible ways to jump these hurdles and develop new gene therapies that may be used alone or in synergy with other modalities to provide a powerful treatment option for patients with GBM.     

Effect of bed head elevation during sleep in symptomatic patients of nocturnal gastroesophageal reflux

Background and Aim: Nocturnal gastro‐esophageal reflux causes heartburn and sleep disturbances impairing quality of life. Lifestyle modifications, like bed head elevation during sleep, are thought to alleviate the symptoms of gastroesophageal reflux. We tested the hypothesis that bed head elevation might decrease recumbent acid exposure compared to sleeping in a flat bed. Methods: Patients of symptomatic nocturnal reflux and documented recumbent (supine) reflux verified by esophageal pH test entered the trial. On day 1, baseline pH was measured while the patient slept on a flat bed. Then patients slept on a bed with the head end elevated by a 20‐cm block for the next 6 consecutive days from day 2 to day 7. The pH test was repeated on day 2 and day 7. Each patient acted as his own control. Results: Twenty of 24 (83.3%) patients with mean age of 36 ± 5.5 years completed the trial. The mean (± SD) supine reflux time %, acid clearance time, number of refluxes 5 min longer and symptom score on day 1 and day 7 were 15.0 ± 8.4 and 13.7 ± 7.2; P = 0.001, 3.8 ± 2.0 and 3.0 ± 1.6; P = 0.001, 3.3 ± 2.2 and 1.0 ± 1.2; P = 0.001, and 2.3 ± 0.6 and 1.5 ± 0.6; P = 0.04, respectively. The sleep disturbances improved in 13 (65%) patients. Conclusions: Bed head elevation reduced esophageal acid exposure and acid clearance time in nocturnal (supine) refluxers and led to some relief from heartburn and sleep disturbance.     

The CT guided transoral approach: A biopsy technique for a poorly differentiated chordoma in a 5 year old

Mass lesions presenting at the craniocervical junction often present a unique challenge due to the complex anatomic arrangement limiting access for tissue diagnosis. The transoral approach has predominantly been used for percutaneous vertebroplasty of high cervical vertebrae with limited literature describing image guided biopsy for bony lesions in this region in the pediatric patient. We describe a technique of computed tomography guided transoral biopsy of a poorly differentiated chordoma located at the C1–C2 level in a 5-year-old child, and review this diagnosis.     

Interaction between cisplatin treated murine peritoneal macrophages and L929 cells: involvement of adhesion molecules, cytoskeletons, upregulation of Ca2+ and nitric oxide dependent cytotoxicity

Murine peritoneal macrophages on treatment with cisplatin (10 microg/ml) showed increased binding to L929 cells. Cisplatin treated macrophage on co-incubation with L929 cells form a distinct cytoplasmic contact between the two cells. The plasmalemmae of the two cells fuse over a large surface area. The formation of contact between the cisplatin treated macrophage and L929 cell results in the induction of apoptosis in L929 cell. Untreated macrophages did not form a contact with L929 cells and no apoptosis is observed in L929 cells. Immunofluorescence microscopical studies clearly show the participation of cytoskeleton and the adhesion molecules in the formation of contact between the two cells. Further, a significant enhancement of the expression of iNOS and cytosolic Ca2+ was observed in cisplatin treated macrophages co-incubated with L929 cells. Cisplatin treated macrophages produced significant amount of NO when co-incubated with L929 cells, while there was minimal production of NO by untreated macrophages co-incubated with L929 cells. Cisplatin treated macrophage-induced L929 cell death was NO dependent, since L-NMMA (500 microM) significantly inhibited the cytotoxicity of L929 cells. The addition of excess L-arginine (2mM) reversed the L-NMMA induced inhibition of NO production and L929 cell cytotoxicity.     

Iodinated curcumin bearing dermal cream augmented drug delivery,antimicrobial and antioxidant activities

Objectives: Curcumin (Cur) exhibits weak microbicidal activity owing to high lipophilicity and low cell permeability. Therefore, in the present investigation, Cur was iodinated using elemental iodine (I₂) to synthesise Cur–I₂ powder that was later formulated as Cur–I₂ dermal cream and characterised in vitro for antimicrobial and antioxidant activities.

Methods and results: Electrophilic addition of I₂ saturated the olefinic bonds of Cur, as confirmed by UV/visible spectroscopy, FT-IR, ¹H NMR and DSC techniques. In addition, in vitro skin permeation and retention analysis indicated that Cur–I₂ cream followed the first order and Higuchi model for drug release through the rat skin. The minimum inhibitory concentration (MIC) of Cur–I₂ powder was measured to be 60 and 90?µg/ml significantly (p?Staphylococcus aureus and Escherichia coli, respectively. Moreover, Cur–I₂ also exhibited strong antioxidant potential.

Conclusions: Cur–I₂ cream warrants further in vivo study to scale up the technology for clinical translation.