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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.

Purpose: We assess the risk of systemic recurrence after retroperitoneal lymph node dissection for clinical stage I nonseminoma germ cell testis tumor based on predominance of embryonal carcinoma and/or vascular invasion in the orchiectomy specimen., Materials and Methods: A total of 292 cases of clinical stage I nonseminoma germ cell testis tumor treated with retroperitoneal lymph node dissection from 1990 to 1995 were identified from the Indiana University database. A minimum of 2 years of followup was required for study entry. Review of the written pathological reports classified tumors as embryonal carcinoma predominant, when it was present at a level greater than any other histology, nonpredominant, when it was present but not as the main histological subtype, and absent. Vascular invasion was categorized as present or absent., Results: Of the 292 cases 226 (77. 4%) were pathological stage I and relapse rate after retroperitoneal lymph node dissection was 10.2%. Vascular invasion and embryonal carcinoma predominance in the orchiectomy specimen were predictors of relapse in this group. None of the 35 pathological stage II cases treated with adjuvant chemotherapy had relapse, whereas relapse occurred in 7 of 31 pathological stage II cases (22.6%) not treated with adjuvant chemotherapy., Conclusions: Pathological stage I cases with predominant embryonal carcinoma and/or vascular invasion in the orchiectomy specimen have a higher probability of systemic recurrence after retroperitoneal lymph node dissection. Dissection alone still has a major therapeutic impact (77%) in patients with clinical stage I, pathological stage II nonseminoma germ cell testis tumor.

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.

Purpose: To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis., Patients and Methods: All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively., Results: Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free., Conclusion: Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.

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.

This study was undertaken to assess the reliability of the endoscopic biopsies in the evaluation of colorectal villous tumors (CRVT). In 163 consecutive patients referred for surgical treatment of CRVT, preoperative evaluation had been routinely done by colonoscopy and multiple biopsies. Tumors were classified in 3 groups: low grade tumors, high grade tumors and adenocarcinomas. Infiltration in depth was staged on the postoperative specimens according to the Dukes-Aster-Coller's classification. All the tumors were completely resected by surgery and definitive pathological diagnosis was established. An exact correlation between the pre- and postoperative staging was observed in 48% of the cases. Accuracy averaged 54% in the group-by-group comparison, with an overstaging rate of 6.7%, and an understaging rate of 39%. The incidence of adenocarcinomas was 22% in the group with clearly benign preoperative biopsies and 50% in the other cases. There were significantly more B2 and C tumors among the patients referred after 3 or more endoscopic attempts (33%) than after one or two sessions (10%) (p < 0.0003). We confirm that in spite of multiple endoscopic biopsies, only a complete resection permits an exact staging and an appropriate therapeutic choice.

Purpose: We assess the benefit of retroperitoneal lymph node dissection for adult paratesticular rhabdomyosarcoma., Materials and Methods: A total of 19 adults with paratesticular rhabdomyosarcoma who underwent retroperitoneal lymph node dissection between 1980 and 1997 comprise our study population. Postoperative chemotherapy was administered in all patients, including cyclophosphamide, doxorubicin and vincristine with or without consolidation with ifosfamide and etoposide in 17, and vincristine, actinomycin D and cyclophosphamide in 2. Radiation therapy also was administered in 2 patients. Patients were classified into pathological and clinical groups according to the Intergroup Rhabdomyosarcoma Studies. Mean followup was 6.4 years (range 0.5 to 17.6)., Results: A total of 17 patients (89%) were disease-free and 2 (1 in pathological group I and 1 in pathological group II) died of disease that recurred outside of the retroperitoneum. Of 16 clinical group I patients 9 were in pathological group II. There were negative nodes in 2 of 3 clinical group II patients. Thus, abdominal computerized tomography correctly staged only 8 of 19 patients (42%)., Conclusions: Retroperitoneal lymph node dissection accurately stages paratesticular rhabdomyosarcoma and eliminates the need for abdominal radiotherapy in patients in pathological group II. Combined modality therapy with retroperitoneal lymph node dissection and postoperative chemotherapy achieves a high cure rate.

The aim of this literature review is to evaluate current data on laparoscopic and open appendicectomy in order to establish a new gold standard in surgery. The authors have reviewed 4190 appendicectomies, 3322 laparoscopic appendicectomies (LA) and 868 open appendicectomies (OA), from 22 studies published between February 1992 and June 1994. Four studies dealt exclusively with pediatric patients (n = 1558). The analysis compares surgical technique, operating time, pathological findings, major and minor complications, postoperative pain and costs. The strongest arguments against LA are the increased rate of major complications, the increase of overall cost and the negative effect of the learning curve. The argument in favour of LA are the significant reduction of minor complications, the shortening of the postoperative hospitalization and of the time to resume full activity. The benefit of LA regarding the amount of analgesia requirement and the time needed to resume normal feeding after surgery is still controversial. The authors have reached the conclusion that LA might emerge as the first choice for appendicectomy. More studies are necessary to confirm this trend.

Background/aims: The present study evaluates both merits and limits of extensive lymph node clearance in the mediastinum and upper abdomen on patients operated on more than 5 years ago., Materials and Methods: One hundred forty-four esophageal cancer patients underwent subtotal (n = 97) or distal (n = 47) esophageal resection more than 5 years ago. Twenty-six patients operated on in a curative attempt were given radiotherapy (n = 14) or radiochemotherapy (n = 12)., Results: Esophagectomy with extensive lymph node clearance was feasible in 102 of the 144 patients (70.8%). In-hospital mortality was 1.4%. Thirty-six patients lived more than 5 years, ie. 25% of all the esophagectomized patients and 35.3% (36/102) of those who were operated on in a curative attempt. Five-year absolute survival was 38.4% after combined therapy v.s. 34.2% after surgery alone (p > 0.05). In the latter instance, it was 57.1% for those patients with normal lymph nodes v.s. 14.6% for those with metastatic lymph nodes, and it was 64% for those with non-transmural tumors v.s. 19.6% for those with transmural tumors. One half of those patients who were not given adjuvant therapy following esophagectomy with extensive lymph node clearance died of neoplastic spread, namely distant metastases (27.6%), cervical spread (3.9%), and local recurrence (10.5%)., Conclusions: Esophagectomy with extensive lymph node clearance is not feasible in 30% of the patients in whom it is attempted, and it does not prevent further neoplastic spread in one half of those in whom it is feasible. It is capable of curing 15 to 20% of those patients with locally advanced neoplasms and shelters 90% of the patients from local recurrence.

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.