Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders

Purpose To investigate the expression of connective tissue growth factor (CTGF) in the retina of human subjects with diabetes mellitus, and CTGF, CD105, and gelatinase B in proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR) epiretinal membranes. Methods Twelve donor eyes from six subjects with diabetes mellitus, 10 eyes from five nondiabetic subjects, 14 PDR membranes, and five PVR membranes were studied by immunohistochemical techniques. In situ zymography was used to examine gelatinolytic activity in four PDR membranes. Results In nondiabetic retinas, there was no immunoreactivity for CTGF. Diabetic retinas showed immunoreactivity for CTGF in ganglion cells and microglia. Vascular endothelial cells in PDR membranes expressed CTGF, CD105, and gelatinase B in 10 (71.4%), 11 (78.6%), and 5 (35.7%) membranes, respectively. Myofibroblasts in PDR membranes expressed CTGF, and gelatinase B in 14 (100%), and 6 (42.9%) membranes, respectively. There was a significant correlation between the number of blood vessels expressing the panendothelial marker CD34 and the number of blood vessels expressing CTGF (r = 0.7884; P = 0.0008), and CD105 (r = 0.6901; P = 0.0063), and the number of myofibroblasts expressing CTGF (r = 0.5922; P = 0.0257). There was a significant correlation between the number of myofibroblasts expressing α-smooth muscle actin and the number of myofibroblaasts expressing CTGF (r = 0.8393; P = 0.0002). In situ zymography showed the presence of gelatinolytic activity in vascular endothelial cells in PDR membranes. Myofibroblasts in PVR membranes expressed CTGF, and gelatinase B. Conclusions These results suggest a possible role of CTGF, CD105, and gelatinase B in the pathogenesis of proliferative vitreoretinal disorders.     

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double‐blind,randomized, placebo‐controlled trial

Objective

To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX).

Methods

The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double‐blind, placebo‐controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet.

Results

In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046).

Conclusion

This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

     

Human hair follicle and interfollicular keratinocyte reactivity to mouse HPV16-transformed cells: an in vitro study

The role of stem cells in cancer formation and spreading has been established. As with normal tissue, the cancer stem cells need a special microenvironment to support their growth. This microenvironment may be represented by the tumor stroma. One of the possible ways of tumor stromal formation is the epithelial-mesenchymal transition of tumor epithelium. Following this mechanism, stromal cells must share the basic genetic alterations with the tumor cells. In an attempt to create a system capable of testing some aspects of the mesenchymal cell-keratinocyte interactions, we studied the effects of the fibroblastoid mouse TC-1 cells that were prepared by the introduction of human papillomavirus type 16 (HPV16) genes E6 and E7 to lung epithelial cells on the phenotype of normal human interfollicular and hair follicle keratinocytes. From this point of view, they may resemble stromal cells formed by the epithelial-mesenchymal transition of cells from HPV-induced squamous cell carcinoma. In contrast to 3T3 murine embryonic fibroblasts which were used as control cells, TC-1 cells influenced not only the size of the keratinocytes and the shape of their colonies, but also induced the expression of keratins 8 and 19 and vimentin. In conclusion, TC-1 cells exhibited a marked biological activity by influencing the behavior of the normal human follicular and intefollicular keratinocytes. This observation is compatible with the hypothesis that stromal cells play an important role in tumor progression and spreading.     

Population clinical pharmacology of children: general principles

Introduction Population modelling using mixed-effects models provides a means to study variability in drug responses among individuals representative of those for whom the drug will be used clinically.Discussion The advantages of these models in paediatric studies are that they can be used to analyse sparse data, sampling times are not crucial and can be fitted around clinical procedures and individuals with missing data may still be included in the analysis. The introduction of explanatory covariates explains the predictable part of the between-individual variability. Simulations using parameter estimates and their variability can be used to investigate large numbers of children – many more than is possible in studies dealing with real children – for a fraction of the cost, which is an advantage when developing clinical trials. Paediatric population modelling has expanded greatly in the past decade and is now a routine procedure during the development and investigation of drugs. Children have benefitted and will continue to benefit from this approach. Financial Support: The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) with a Clinical Doctoral Grant (A 6/5-KV-G 1).     

Liver, meconium, haemorrhage: the value of T1-weighted images in fetal MRI

Background Ultrafast T2-weighted (T2-W) MRI sequences are currently considered a routine technique for fetal MR imaging. Limited experience exists with fetal T1-weighted (T1-W) imaging techniques.Objective To determine MRI patterns of some fetal abdominal or haemorrhagic disorders with particular respect to the diagnostic value of T1-W images.Materials and methods In addition to standard T2-W single-shot sequences, T1-W single-shot and/or multislice sequences were employed in 25 MR examinations performed in 23 fetuses between 20 and 36 weeks of gestation for more detailed assessment of liver, meconium-filled digestive tract, haemorrhage, or further characterization of a fetal abdominal mass. Diagnostic value and presence of motion artefacts on T1-W images was recorded in each case.Results T1-W images enabled superior delineation of fetal liver and large intestine. They provided additional diagnostic information in 9 (39%) of 23 fetuses. One false-positive and one false-negative MRI diagnosis of malrotation anomaly were encountered. Use of single-shot T1-W sequences reduced the occurrence of motion artefacts in 64%.Conclusion Our results suggest that the specific signal properties of methaemoglobin, meconium and liver are sufficiently important for T1-W sequences to become a routine part of fetal MRI protocols when dealing with digestive tract anomalies, diaphragmatic and abdominal wall defects, intraabdominal masses, and fetal haemorrhage.     

Oral complications of bone marrow transplantation

The procedures used to condition patients with acute leukemia for bone marrow transplantation and the prolonged delay in recovery of normal hematologic and immunologic capacities often have troublesome complications affecting the mouth and associated structures. Early recognition and prompt effective control of these oral complications are crucial to the successful outcome of bone marrow transplantation.