Cellular kinetics of prednimustine versus chlorambucil plus prednisolone in vitro

Summary Intracellular concentrations of prednimustine (PM), chlorambucil (CLB), phenylacetic acid mustard (PAAM) and prednisolone (P) were measured in different experimental tumor cell lines that had been incubated with either PM or CLB+P. For intracellular analytical determination, we modified a high-pressure liquid chromatographic method for the detection of these substances in plasma. Intact PM could be detected in the intracellular compartment of the incubated tumor cells. PM-incubated cells from PM-injected rats exhibited a higher intracellular concentration-time integral (PAAM) and longer concentration-time profiles for drugs with alkylating capacity than did cells exposed to the CLB+P mixture or to CLB. PAAM was not detectable after incubation of cells with PM, whereas in CLB-incubated cells the AUC of PAAM exceeded that of the parent drug CLB. Our in vitro results therefore favour the concept of a facilitated intracellular uptake and an increased antiproliferative effect for PM versus CLB and CLB+P.Dedicated to Prof. Dr. H. J. Dengler on the occasion of his 65th birthday. This study was supported by the Ministry of Science and Research of Nordrhein-Westfalen     

Cervicobrachial syndrome--work and disability.

The subjects in the study were 114 persons receiving a disability pension or referred for disability assessment. They were placed in two groups of 57 persons each, one with marked cervicobrachial syndrome and the other without. The latter group was chosen by the method of equivalent pairs with regard to sex and age. All subjects underwent a clinical examination and a standardized questionnaire was completed. The questionnaire pertained to the state of health, focussing on the amount and type of physical burdening at the workplace and on activities outside the workplace. Sixty-five percent of the subjects were aged from 51 to 60 years. A statistically significant difference was established between earlier occupation and cervicobrachial syndrome. Cervicobrachial syndrome was found in 31.6% of unskilled workers and 12.3% of the controls (P < 0.05). A forced body posture during work was recorded in 74% of the subjects with the syndrome and in 50% of the control subjects (P < 0.05). Repetitive movements at work were reported by a large number of subjects with cervicobrachial syndrome (71.9:49.1%; P < 0.05) who also claimed to strain the arms (84.2:61.4%; P < 0.05) and burden the cervical spine (68.5:40.4%; P < 0.05) during household activities to a significantly greater extent than the controls. A possible preventive approach to the occurrence and progression of cervicobrachial syndrome is discussed.     

Changes in the anterior segment of the eye in workers in the coke manufacturing industry

An investigation carried out of eye disorders in workers employed in the manufacture of coke demonstrated a high percentage of changes in the anterior segment of the eye. Registered symptoms such as conjunctival hyperemia, pinguecula, pigmentation and conjunctivitis were most probably connected with specific work and exposure to coal dust and irritants. In workers exposed for less than two years there were no changes in lacrimal secretion. In those working for 2-7 years excessive hypersecretion dominated, and after a longer period of exposure the majority of workers had hyposecretion.     

Countertransference and empathic problems in therapists/helpers working with psychotraumatized persons

Countertransference in therapists working with patients with posttraumatic stress disorder (PTSD) differs from countertransference in other psychotherapeutical settings. In this article we discuss the specificities of counter- transference in treating PTSD patients and its relation to empathy. The most difficult countertransference problems occur in treating multiply traumatized patients. Countertransference may occur towards an event (e.g., war), patients who have killed people, as well as to colleagues who avoid treating PTSD patients, or towards a supervisor who avoids, either directly or indirectly, supervision of therapists working with PTSD patients. Our recommendation for the prevention of problems in treating PTSD patients include : 1) careful selection of the therapist or helper, both in the personality structure and training; 2) prevention by debriefing and team work and peer supervision; and 3) education - theoretical, practical, and therapeutical.     

Synthesis and characterization of acrylate-terminated unsaturated copolyesters

The reaction of the potassium salt of acrylic acid with the potassium salt of a dicarboxylic acid and 1,4-dibromobutane was applied to the synthesis of three series of acrylate-terminated copolyesters: poly(tetramethylene maleate-co-tetramethylene phthalate) (BMPA), poly(tetramethylene fumarate-co-tetramethylenephthalate) (BFPA) and poly(tetramethylene phthalate-co-tetramethylene succinate) (BPSA). The monofunctional monomer, the potassium salt of acrylic acid, was used for the introduction of double bonds at the end of the chains and for the regulation of the molecular weight of the polyesters. The telechelic copolyesters were characterized by ¹H and ¹³C NMR spectroscopy, in almost all cases providing an acrylate functionality of two.     

Cyclodextrin encapsulation of daidzein and genistein by grinding: implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts

This work aimed to investigate the potential effect of cyclodextrin encapsulation on intrinsic ability of daidzein (DAD) and genistein (GEN) to inhibit the glycosaminoglycan (GAG) synthesis in fibroblasts originating from patients with mucopolysaccharidosis (MPS), type II and III. DAD or GEN encapsulation with either 2-hydroxypropyl-β-cyclodextrin or sulphobuthylether-β-cyclodextrin were achieved by neat grinding and were characterised by thermal analysis, X-ray powder diffraction, scanning electron microscopy and solubility testing which confirmed the complexes formation with increased solubility with respect to starting compounds. Both isoflavones, as well as their co-ground cyclodextrin complexes reduced GAG levels in the fibroblasts of MPS II and MPS III patients from 54.8–77.5%, in a dose dependent manner, without any significant cytotoxic effect. Cyclodextrin encapsulation did not change the intrinsically high effect of both DAD and GEN on the GAG level reduction in the treated cells, thus could be considered as a part of combination therapies of MPS.     

Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia

X-linked hypohidrotic ectodermal dysplasia (XLHED; ectodysplasin deficiency) has been classically described as affecting hair, sweat glands, and dentition. What may be underappreciated is the effect ectodysplasin deficiency has on glands surrounding the airways and eyes and the resulting chronic health issues. In this study, 12 male children (age range 6–13 years) and 14 male adults with XLHED (18–58 years of age) were investigated by pulmonary function tests, measurement of fractional exhaled nitric oxide, and by ophthalmologic assessments. Twelve healthy individuals (six children, six adults) served as controls. Signs of airway constriction and inflammation were detected in eight children with XLHED, including the youngest subject, and in ten adult XLHED patients. Increased tear osmolarity, reduced tear film break-up time, and other ocular abnormalities were also present at an early age. Five of 12 XLHED subjects not reporting a history of asthma and 7 of the 12 patients not reporting a history of dry eye issues showed at least two abnormal test results in the respective organ system. The presence of residual sweat ducts, suggestive of partial ectodysplasin gene expression, correlated with milder disease in two XLHED subjects with mutations affecting the collagen-like domain of ectodysplasin. Conclusion: The high prevalence of asthma-like symptoms in XLHED patients as young as 6 years and a similar prevalence of dry eye problems indicate that screening evaluation, regular monitoring, and consideration of therapeutic intervention should begin in early childhood.     

Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury

ABSTRACT: BACKGROUND: : Using live imaging approach we have previously shown that microglia activation after stroke is characterized by marked and long-term induction of the Toll like Receptor 2 (TLR2) biophotonic signals. However, the role of TLR2 (and potentially other TLRs), beyond the acute innate immune response and an early neuroprotection against ischemic injury is not well understood. METHOD: S: The TLR2 -/- mice were subjected to transient middle cerebral artery occlusion (MCAO) followed by different reperfusion times. Analyses assessing microglial activation profile/innate immune response were performed using in situ hybridization, immunohistochemistry analysis, flow cytometry and inflammatory cytokine array. The effects of the TLR2 deficiency on the evolution of ischemic brain injury were analyzed using a cresyl violet staining of brain sections with appropriate lesion size estimation. RESULTS: : Here we report that TLR2 deficiency markedly affects post-stroke immune response resulting in delayed exacerbation of the ischemic injury. The temporal analysis of the microglia/macrophage activation profiles in TLR2 -/- mice and age-matched controls revealed reduced microglia/macrophage activation after stroke, reduced capacity of resident microglia to proliferate as well as decreased levels of MCP-1 and consequently lower levels of CD45high/CD11b+ expressing cells as shown by flow cytometry analysis. Importantly, although acute ischemic lesions (24-72hrs) were smaller in TLR2 -/- mice, the observed alterations in innate immune response were more pronounces at later time-points (at day 7) after initial stroke, which finally resulted in delayed exacerbation of ischemic lesion leading to larger chronic infarctions as compared to WT mice. Moreover, our results revealed that TLR2 deficiency is associated with significant decrease in the levels of neurotrophic/antiapoptotic factor IGF-1, expressed by microglia in the areas in- and around ischemic lesion. CONCLUSION: Altogether our results clearly suggest that optimal and timely microglial activation/innate immune response is needed to limit neuronal damage after stroke.