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The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized (S)-3-[3,4-difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca(2+) mobilization; and leukocyte chemotaxis toward MCP-1 (IC(50) = 7-97 nM), whereas it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a noncompetitive mode of action. JNJ-27141491 blocked the binding of (125)I-MCP-1 to human monocytes (IC(50) = 0.4 microM), but it failed to affect MCP-1 binding to mouse, rat, and dog cells (IC(50) > 10 microM). Therefore, transgenic mice, in which the mouse (m)CCR2 gene was replaced by the human counterpart, were generated for in vivo testing. In these mice, oral administration of JNJ-27141491 dose-dependently [5-40 mg/kg q.d. (once daily) or b.i.d.] inhibited monocyte and neutrophil recruitment to the alveolar space 48 h after intratracheal mMCP-1/lipopolysaccharide instillation. Furthermore, treatment with JNJ-27141491 (20 mg/kg q.d.) significantly delayed the onset and temporarily reduced neurological signs in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Taken together, these results identify JNJ-27141491 as a noncompetitive, functional antagonist of hCCR2, capable of exerting oral anti-inflammatory activity in transgenic hCCR2-expressing mice.

We recently reported the discovery of a series of 2-thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5-diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5-membered heterocyclic substituents at the 4-position gave highly potent CCR2 antagonists. Hydrolysis of the 5-ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.

Objectives: If fetal ECG (fECG) devices could be miniaturized sufficiently, one could consider their implantation at the time of fetal surgery to allow permanent monitoring of the fetus and timely intervention in the viable period. We set up an experiment to evaluate the feasibility of in utero direct fECG monitoring and telemetric transmission using a small implantable device in a lamb model., Methods: A 2-lead miniature ECG sensor (volume 1.9 cm(3); weight 3.9 g) was subcutaneously implanted in 2 fetal lambs at 122 days gestation (range 119-125; term 145 days). The ECG sensor can continuously register and transmit fECG. The signal is captured by an external receiving antenna taped to the maternal abdominal wall. We developed dedicated software running on a commercial laptop for on-line analysis of the transmitted fECG signal. This was a noninterventional study, i.e. daily readings of the fECG signal were done without clinical consequences to the observations., Results: fECG could be successfully registered, transmitted by telemetry and analyzed from the moment of implantation till term birth in one case (24 days). In the second case, unexplained in utero fetal death occurred 12 days after implantation. In this subject, agonal fECG changes were recorded., Conclusion: An implanted miniature (<2 ml) ECG sensor can be used to retrieve, process and transmit continuously a qualitative fECG signal in third-trimester fetal lambs. The telemetric signal could be picked up by an external antenna located within a 20-cm range. In this experiment, this was achieved through taping the external receiver to the maternal abdomen. Any acquired signal could be transmitted to a commercially available laptop that could perform on-line analysis of the signal., ((c) 2008 S. Karger AG, Basel.)

In order to fit human body, flexibility, or even better stretchability is requested for biomedical systems like implants or smart clothes. A stretchable electronic technology has been developed. This can provide highly stretchable interconnections fully compatible with PCB technologies. In order to prove the feasibility of complex biomedical systems like inner body implants or wearable systems, a variety of stretchable systems has been designed from sensor to power source systems.

The aim of this study was to further define the clinical features of subcortical aphasia in children with deep brain infarcts and to define the sequelae associated with childhood strokes. We retrospectively studied nine children with left subcortical brain infarcts who presented with acquired language disorder and underwent language investigations based on standardized tests. Stroke in these patients involved the left internal capsule, lenticular or thalamic nuclei, or a combination of these. Early aphasic manifestations following the deep cerebral infarcts affected language expression. These included mutism, nonfluent speech, word finding difficulties, and phonemic and semantic paraphasia. Speech comprehension was generally more preserved. All patients subsequently improved, although variably; sequelae such as dysfluency, word finding difficulties, and written language learning impairment could be detected through standardized tests in six of them (all younger than 6 years at the time of the infarct). Two of the three remaining patients (both older than 6 years at the time of the infarct) had a full recovery. Our study confirms the concept of childhood subcortical aphasia, depicts the linguistic profile in these patients, and sustains the indication of systematic formal language assessment during the follow-up of all children with subcortical infarct involving the dominant hemisphere.

We describe the synthesis and SAR of a new class of CCR2 antagonists based on 2-mercaptoimidazole scaffold. The initial lead 1a was optimized to the 3,4-disubstituted analogues 1p-(S) and 1q-(S), which have IC(50) values in the MCP-1 induced Ca-flux below 0.01 microM.

The neolignan-type substance 2,4-dimethyl-3,5-bis(4'-methoxyphenyl) tetrahydrofuran is presented as a new forensic marker compound for the peracid oxidation of anethole. It is hypothesized that the formation of a stable intermediary carbocation in the hydrolysis reaction of anethole epoxide is not only responsible for the presence of 1,2-diols (and its esters) and 4-methoxyphenyl-2-propanone (PMP2P) but can also be the cause for the creation of this neolignan impurity due to interaction with anethole itself. Moreover, the applicability of this new forensic marker is demonstrated by its retrieval in clandestinely manufactured 4-methoxyamphetamine (PMA) preparations.

The recent ruling of the European Court of Justice in the case Smits-Peerbooms explicitly mentions undue delay as a legitimisation for cross-border care within the EU. In the Netherlands, waiting times are well above the norm set by several health care parties as well as maximally acceptable waiting times elicited in patients. This might indicate that Dutch patients are often entitled to care in other Member States, in the sense that insurers cannot withhold reimbursement of cross-border care in the present situation. However, experiments clearly demonstrate that few Dutch patients are willing to travel abroad. Patients seem to prefer longer waiting in the Netherlands over shorter waiting by going abroad, even those living in border regions. In addition, mobility of patients within the Netherlands is very modest. Given this inertia in patient mobility, in the short run, cross-border care will probably remain an insignificant phenomenon in terms of quantities of patients travelling abroad and therefore the impact of the Smits-Peerbooms rulings is limited.

The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF(164/164) mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF(120/120) mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF(188/188) mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF(164), was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.

Purpose: We evaluated the clinical behavior of clinical stage I pure yolk sac tumor of the testis in adults to determine whether the behavior of this entity is different than that of clinical stage 1 nonseminoma., Materials and Methods: We searched the testis cancer database at our institution for adults with clinical stage I pure yolk sac tumor of the testis who underwent retroperitoneal lymph node dissection. We identified 12 such patients and reviewed the database and hospital charts to determine clinical behavior., Results: Disease was pathological stage I in 8 of the 12 patients (66%), including 1 with recurrence after retroperitoneal lymph node dissection. Disease was pathological stage II in 14 patients (33%), including 1 who remains disease-free after electing adjuvant bleomycin, etoposide and cisplatin. Of the 3 patients who elected observation after retroperitoneal lymph node dissection only 1 has had recurrence, while 2 (66%) were cured by retroperitoneal lymph node dissection only., Conclusions: Contrary to juvenile yolk sac tumor, which has a strong tendency toward hematogenous metastasis, the behavior of clinical stage I adult pure yolk sac tumor is similar to that of all other stage I nonseminomas in adulthood.

Interleukin (IL)-5 regulates the growth, differentiation, and activation of eosinophils. When activated, eosinophils release an array of proinflammatory and cytotoxic products and act as prominent effector cells in the process of allergic inflammation. Depriving eosinophils of IL-5 may therefore represent a viable approach to treat allergic disorders. This study describes the identification of R146225, a novel six-substituted azauracil derivative, as a potent, orally active inhibitor of IL-5 biosynthesis, capable of reducing pulmonary eosinophilia in mice. In vitro, R146225 inhibited IL-5 protein formation by activated human whole blood (IC(50) = 34 nM), human peripheral blood mononuclear cells (IC(50) = 24 nM), and murine spleen cells (IC(50) = 6 nM). In contrast, the compound enhanced generation of interferon-gamma and had little or no inhibitory effect on the production of IL-2 and IL-4. Reverse transcription-polymerase chain reaction analysis of stimulated whole blood cells indicated R146225's ability to down-regulate IL-5 mRNA expression. In vivo p.o. administration of R146225 (2.5 mg/kg) to mice before an i.v. anti-CD3 antibody challenge reduced IL-5 but enhanced interferon-gamma serum levels, without affecting IL-2 and IL-4 production. Analogous to the in vitro results, R146225 suppressed splenic IL-5 mRNA expression, while message levels of the other cytokines remained unchanged. Moreover, p.o. dosing of R146225 (0.6-2.5 mg/kg) dose dependently reduced the pulmonary accumulation of eosinophils induced in mice by an intranasal instillation of Cryptococcus neoformans. Based on these data, R146225 may be useful in the therapy of eosinophil-driven allergic conditions.

Defective law making (processes) is considered as one of the main problems in reforming health care systems in Central and Eastern Europe. To improve this situation, authors propose a theoretical method of law making advocating progressive legislative changes. Reflected by a simplified model such a method integrates the functions of health care law into a general concept of law making. Such a theoretical concept reflects both normative and instrumental qualities and can support the legislature in redefining health care legislation in a more rational manner. Particularly in a state of flux with rapid and profound changes, rational decision-making in law making activity could enhance the success of intended health care reforms.

Study Design: In 100 consecutive patients who underwent surgery because of soft cervical disc herniation, the sagittal and transverse diameters, the area of the bony cervical spinal canal, the sagittal diameter of the hernia, and the minimal bony intervertebral foramen diameter were measured by computed tomography. The data were compared with measurements from a control group of 35 matched healthy individuals., Objectives: To evaluate the relation between the severity of concurrent neurologic symptoms and the sagittal and transverse diameters, the cross-sectional area of the bony spinal canal, the sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in patients with soft cervical disc herniation., Summary of Background Data: Traumatic injury and spondylotic changes have a far greater impact on the spinal cord and nerve roots if the sagittal diameter of the bony cervical spinal canal is small. However, in the case of soft cervical disc herniation, no computer tomographic measurements are available for sagittal and transverse diameters, cross-sectional area of the bony spinal canal, sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in relation to the severity of concurrent neurologic symptoms., Methods: Computed tomography was used to measure sagittal and transverse diameters, cross-sectional area of the bony cervical spinal canal, sagittal diameter of the hernia, and diameter of the minimal bony intervertebral foramen in 100 patients with symptomatic monosegmental cervical soft disc herniation. All patients had undergone an anterior discectomy with removal of the hernia and subsequent interbody fusion using an autologous bone graft taken from the iliac crest., Results: A mean sagittal diameter of the bony cervical spinal canal of 12.9 mm was found, indicating a certain degree of developmental stenosis. Patients with motor disturbances had a significantly smaller sagittal diameter of the bony spinal canal than did patients without motor disturbances. There was a linear correlation between the sagittal diameter of the bony cervical spinal canal and that of the hernia. The sagittal diameter, the area of the bony spinal canal, and diameter of the minimal bony intervertebral foramen were significantly smaller in patients with soft cervical disc herniation than in the control group., Conclusions: Results from this study strongly suggest that the degree and severity of neurologic symptoms accompanying cervical soft disc herniation are inversely related to the sagittal diameter and the area of the bony cervical spinal canal. The latter area is reduced in cases of developmental stenosis or because of soft disc herniation. Moreover, patients with soft cervical disc herniation have a significantly smaller sagittal diameter of the bony spinal canal, a significantly smaller minimal bony intervertebral foramen diameter, and a significantly smaller cross-sectional area of the bony cervical canal than do healthy matched individuals.

Accurate preoperative staging is important for adequate selection of patients for radical prostatectomy. We reviewed the preoperative PSA levels of 214 patients who underwent radical retropubic prostatectomy and analysed the results in relation to pathological stage. 32 (15%) patients had a PSA level below 4 ng/ml; nevertheless 8 of them had already a extracapsular disease and one present with positive lymph nodes. Thus, although a specificity of 90%, the sensitivity is only 18%. 98 (46%) patients had PSA levels beyond 10 ng/ml of which 47 (48%) had extracapsular tumor; this gives a specificity of 62% and a sensitivity of 59%. Finally 35 (16%) patients had a PSA over 20 ng/ml of which 18 (51%) present a extracapsular disease thus the specificity is 87% but the sensibility remains low at 23%. We concluded that although PSA levels are grossly related to the pathological stage, that relation is not reliable to distinguish patients with organ-confined from those who have extracapsular tumor extension and for either definition of a positive PSA level many patients would be denied a curative operation. Therefore, PSA value cannot be used to decide whether to recommend radical prostatectomy for potential cure.

Osteoradionecrosis (ORN) of the mandible is a serious sequel to radiotherapy administered for malignant neoplasms of the head and neck. In a retrospective/prospective study, 28 patients with mandibular defects due to ORN were reviewed. Monocortical and bicortical defects as well as pathological fractures were reconstructed by means of a free serratus anterior/rib (n = 8) or a vascularised iliac crest flap (n = 25). All the former survived; a pathological fracture, however, occurred postoperatively in 2 of the patients (25%). Five iliac crests were lost (20%). The remaining bone struts healed well. The donor site morbidity was very low. Clinical and radiological longterm follow-up showed that a very acceptable functional and cosmetic result was achieved in all cases. Progress of ORN was prevented in ca. 90% of all patients. The radiological follow-up was facilitated with the use of high-resolution CT-scans.

Computed tomographic images, made about 6 months after the repair of fistulas of the lateral semicircular canal with a mixture of bone dust and physiologic adhesive, show the bony density of the reconstructed part of the canal.