Diagnosis of somatisation: effect of an educational intervention in a cluster randomised controlled trial.

BACKGROUND: Somatisation is highly prevalent in primary care (present in 25% of visiting patients) but often goes unrecognised. Non-recognition may lead to ineffective treatment, risk of iatrogenic harm, and excessive use of healthcare services. AIM: To examine the effect of training on diagnosis of somatisation in routine clinical practice by general practitioners (GPs). DESIGN OF STUDY: Cluster randomised controlled trial, with practices as the randomisation unit. SETTING: Twenty-seven general practices (with a total of 43 GPs) in Vejle County, Denmark. METHOD: Intervention consisted of a multifaceted training programme (the TERM [The Extended Reattribution and Management] model). Patients were enrolled consecutively over a period of 13 working days. Psychiatric morbidity was assessed by means of a screening questionnaire. GPs categorised their diagnoses in another questionnaire. The primary outcome was GP diagnosis of somatisation and agreement with the screening questionnaire. RESULTS: GPs diagnosed somatisation less frequently than had previously been observed, but there was substantial variation between GPs. The difference between groups in the number of diagnoses of somatisation failed to reach the 5% significance (P = 0.094). However, the rate of diagnoses of medically unexplained physical symptoms was twice as high in the intervention group as in the control group (7.7% and 3.9%, respectively, P = 0.007). Examination of the agreement between GPs' diagnoses and the screening questionnaire revealed no significant difference between groups. CONCLUSION: Brief training increased GPs' awareness of medically unexplained physical symptoms. Diagnostic accuracy according to a screening questionnaire remained unaffected but was difficult to evaluate, as there is no agreement on a gold standard for somatisation in general practice.     

Retroperitoneoskopie – Erfahrungen mit den ersten 200 Fällen

Zusammenfassung. Der retroperitoneale Zugang findet breite Anwendung bei offenen Operationen in der Urologie. Mit Einführung der Ballondissektionstechnik konnte dieser anatomische Zugang auch für laparoskopische Operationen genutzt werden. Material und Methode: Zwischen 12/1992 und 10/1997 wurden 200 retroperitoneale Operationen an 197 Patienten (Alter 4–82 Jahre) durchgeführt: 78 Nephrektomien, 50 Nierencystenresektionen, 14 Nephropexien, 11 Ureterolysen, 8 retroperitoneale Lymphadenektomien, 8 Nierenbiopsien, 6 Adrenalektomien, 6 Heminephrektomien, 6 Pyeloplastiken, 5 Ureterolithotomien, 6 Ureterocutaneostomien sowie 2 andere. 38 Patienten (19 %) waren bereits abdominell , 22 (11 %) an Niere und Ureter voroperiert. Die Pr?paration des Retroperitonealraums erfolgte in 14 F?llen mit Hilfe eines Ballonkatheters, in 93 F?llen mittels eines Ballontrokarsystems, w?hrend in den letzten 93 F?llen eine Pr?paration des Retroperitoneums mit dem Zeigefinger sich als ausreichend erwies. Ergebnisse: Die Eingriffe wurden wie folgt klassifiziert: 76 einfache Operationen (z. B. Nierenbiopsie, Nierencystenresektion, Ureterocutaneostomie), 102 schwierige (z. B. Adrenalektomie, Nephrektomie, Nephropexie) und 22 sehr schwierige Eingriffe (z. B. Pyeloplastik, Heminephrektomie, Lymphadenektomie). W?hrend der ersten 50 F?lle zeigte sich eine signifikante Lernkurve, welche sich in einer h?heren Operationszeit und Komplikations- sowie Konversionsrate widerspiegelte. Abh?ngig vom Schwierigkeitsgrad des Eingriffs betrugen die mittlere Operationszeiten 45–100 min bei leichten Eingriffen, 95–185 min bei schwierigen und 185–240 min bei sehr schwierigen Operationen. In den letzten 50 F?llen war die Komplikations-, Konversions- sowie Reinterventionsrate mit offenen Eingriffen vergleichbar (2, 4 und 2 %). Schlu?folgerung: Nach mehr als 200 retroperitoneoskopischen Eingriffen wurde die Zugangstechnik bedeutend vereinfacht, so da? das Verfahren heute standardisiert, sicher und reproduzierbar ist.      

Evaluation of stromal metalloproteinases and vascular endothelial growth factors in a spontaneous metastasis model

This study aims to investigate MMP2 and MT1-MMP protein as well as VEGF-C and VEGF-D mRNA expression in tumor cells and distant organs considered to be targets for metastasis in a tumor spontaneous metastasis model previously described. Cultured tumor cells, able to express pro-MMP2, MMP2, pro-MMP9, and MT1-MMP, develop tumor growth and metastasis, mainly in the liver and spleen, when they are injected in the mammary pad gland of Wistar rats. Immunohistochemical studies of tumor masses showed small groups of tumor cells staining for MT1-MMP but not for MMP2. In the liver, tumor metastatic foci and a stromal positive staining for both MMP2 and MT1-MMP were shown. The spleen and lymph nodes, with only scattered metastatic cells, did not show MMPs immunostaining. Using RT-PCR, a significantly higher VEGF-C and VEGF-D gene expression was shown in the liver of tumor-bearing rats respect to normal rats, whereas spleen and lymph nodes did not show significant differences in mRNA VEGF-C/D levels. Taken together, our results suggest that the stroma microenvironment of target organs for metastasis has the ability to produce MMPs and VEGFs that facilitate the anchorage of tumor cells and promote tumor cell growth and angiogenesis.     

Treatment of Peyronie's disease by extracorporeal shockwave therapy: evaluation of our preliminary results

BACKGROUND: Peyronie's disease is an idiopathic disorder of the penis that produces erectile dysfunction. It affects mainly the tunica albuginea. We describe our preliminary results with extracorporal shockwave therapy (ESWT) as a new noninvasive modality for the treatment of Peyronie's disease. PATIENTS AND METHODS: In this study, 24 patients aged 36 to 67 years were treated with ESWT on the Lithostar overhead-module (Siemens). All our patients had unsuccessful medical treatment before ESWT. The average plaque was 7x15 mm. The number of shockwaves ranged from 15,000 to 25,000 (18-21 kV) delivered in four to ten sessions. Most patients needed local anesthesia before therapy. RESULTS: Four patients (17%) showed marked improvement and complete remission of the penile deviation. Six patients (25%) showed partial remission with painless erections after treatment. Four patients had painless erections after treatment but still had some penile deviation. In 10 patients (41%), ESWT failed, necessitating subsequent penile surgery. CONCLUSIONS: Our preliminary results with a response rate of 59% with ESWT for Peyronie's disease, including a 17% complete remission rate, is encouraging. However, further multicenter studies will have to prove if ESWT is a real therapeutic option for this disease.     

Inhibition of inducible nitric oxide synthase gene expression and nitric oxide synthesis in vascular smooth muscle cells by granulocyte-colony stimulating factor in vitro.

Clinical and experimental evidence suggests that granulocyte-colony stimulating factor (G-CSF) acts as an anti-inflammatory modulator with beneficial effects in severe inflammatory diseases, e.g., sepsis and septic shock. Excessive production of nitric oxide (NO) is regarded as a potent mediator of the vascular changes leading to systemic hypotension that occurs during sepsis. Therefore, the aim of the present study was to investigate the influence of G-CSF on inducible nitric oxide synthase (iNOS) gene expression and NO synthesis in vascular smooth muscle cells (VSMC). Qualitative and quantitative analyses of iNOS cDNA revealed that G-CSF significantly reduced interferon-gamma/lipopolysaccharide (IFN-gamma/LPS) dependent iNOS gene expression (P < 0.05) following 6, 18, 24, and 48 h incubation periods. In addition, the co-application of G-CSF resulted in a decreased IFN-gamma/LPS mediated iNOS protein generation as detected by immunoblotting methods after 24 and 48 h. Measurement of the stable NO metabolites showed a significant reduction of nitrite/nitrate concentrations following co-incubation of VSMC with G-CSF + IFN-gamma/LPS (242.57 +/- 10.73 nmol NO2-/NO3-/mg cell protein, n = 8) as compared to IFN-gamma/LPS treatment (306.20 +/- 19.26 nmol NO2-/NO3-/mg cell protein, n = 8, P < 0.05) following a 24-h incubation protocol. This inhibitory effect of G-CSF was still present after a 48 h incubation period (G-CSF + IFN-gamma/LPS: 319.56 +/- 6.26 nmol NO2-/NO3-/mg cell protein; IFN-gamma/LPS: 489.20 +/- 27.15 nmol NO2-/NO3-/mg cell protein (P < 0.05), n = 8, respectively). The present findings suggest that inhibition of iNOS gene expression and NO generation in VSMC might be one of the protective anti-inflammatory effects of G-CSF during sepsis.     

Laparoscopic Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Tumors: Indications and Limitations

Purpose

We describe our experience with laparoscopic retroperitoneal lymph node dissection in 26 patients with nonseminomatous germ cell tumors: 17 had stage I disease with no clinical (computerized tomography, ultrasound or tumor markers) evidence of metastases and 9 (2 with stage IIb and 7 with stage IIc disease) had residual tumor after chemotherapy but with negative tumor markers. Laparoscopic dissection was performed to assess more fully pathological status of the relevant retroperitoneal lymph nodes in both groups.

Materials and Methods

The patient was positioned and trocars were introduced at sites similar to that used for transperitoneal laparoscopic nephrectomy (flank position with 3, 10 mm. and 2, 5 mm. ports). After the white line of Toldt was incised and the colon was reflected anteromedially, the retroperitoneal space was exposed. The landmarks of lymph node dissection were then isolated, including the ureter, aorta, inferior vena cava and both renal veins. Lymph node dissection was performed identical to that for open surgery, with a modified template including the paracaval, interaortocaval, upper preaortic and right common iliac nodes for right tumors, and para-aortic and upper preaortic nodes for left tumors. Lymph node chains were retrieved with a small organ bag.

Results

The procedure was completed successfully in 16 of 17 patients with stage I disease (mean duration 268 minutes for the left and 312 minutes for the right sides). No intraoperative complications were encountered. One patient had delayed ureteral stenosis requiring operative repair, 1 had a pulmonary embolism with an uneventful outcome and 1 who underwent laparoscopic retroperitoneal lymph node dissection on the right side later had retrograde ejaculation. Embryonal carcinoma was found in 1 of the 17 patients.Average postoperative hospital stay was 4.5 days for patients without complications or conversion to an open procedure. After a median followup of 27 months no patient had regional relapse but 2 had pulmonary metastases that were treated successfully with 3 cycles of platinum based chemotherapy. Laparoscopic dissection was significantly more difficult in patients with stage II tumors after chemotherapy. Only in 2 patients with stage IIb disease was laparoscopic lymphadenectomy successful. In 5 of the 7 patients with stage IIc cancer portions of the dissection had to be done after conversion to an open (conventional) operation via a small incision (suprainguinal or pararectal). In 1 patient the laparoscopic approach was completely abandoned and converted to an open operation via a standard midline incision. In all 9 cases histopathological examination revealed complete necrosis. No patient has evidence of disease.

Conclusions

Our preliminary experience suggests that a modified laparoscopic retroperitoneal lymph node dissection is feasible for stage I tumors. However, it cannot be recommended after previous chemotherapy (stages IIb and IIc disease).     

Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506

BACKGROUND: Recently, specific immunonutrients were found to increase experimental allograft survival when combined with cyclosporine A (CsA). This study compared the effect on rat cardiac allograft survival when nutritional immunomodulation was used with CsA, rapamycin (Rapa), or tacrolimus (FK506). METHODS: Intra-abdominal ACI to Lewis cardiac allografts were performed and assessed daily by palpation. Study groups included untreated controls and those receiving CsA, Rapa, or FK506. Rats were fed ad libitum with Impact diet (fortified with fish oil, arginine, and RNA) or standard rat food. Further study groups were transplanted that received a donor-specific transfusion in addition to immunosuppression and diet. RESULTS: Allograft survival was extended by combining Impact with CsA (45.3+/-19 days) and Rapa (165.3+/-52 days), but not FK506 (12.4+/-3.2 days). Mean graft survival in the Rapa/Impact group met criteria for functional tolerance. The addition of a donor-specific transfusion did not lead to graft survival advantages over similar groups not receiving a donor-specific transfusion. CONCLUSIONS: The use of immunonutrients improves transplant outcome in animals treated with short courses of CsA and Rapa, but not FK506. These findings highlight the potential differences in the effects of nutritional immunomodulation with different immunosuppressive drugs in the treatment of transplant patients.     

Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study

Background

The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. A physiologically based pharmacokinetic (PBPK) model for pediatric rivaroxaban dosing has been constructed.

Methods

We quantitatively assessed the pharmacokinetics (PK) of a single rivaroxaban dose in children using population pharmacokinetic (PopPK) modelling and assessed the applicability of the PBPK model. Plasma concentration–time data from the EINSTEIN-Jr phase I study were analysed by non-compartmental and PopPK analyses and compared with the predictions of the PBPK model. Two rivaroxaban dose levels, equivalent to adult doses of rivaroxaban 10 mg and 20 mg, and two different formulations (tablet and oral suspension) were tested in children aged 0.5–18 years who had completed treatment for VTE.

Results

PK data from 59 children were obtained. The observed plasma concentration–time profiles in all subjects were mostly within the 90% prediction interval, irrespective of dose or formulation. The PopPK estimates and non-compartmental analysis-derived PK parameters (in children aged ≥6 years) were in good agreement with the PBPK model predictions.

Conclusions

These results confirmed the applicability of the rivaroxaban pediatric PBPK model in the pediatric population aged 0.5–18 years, which in combination with the PopPK model, will be further used to guide dose selection for the treatment of VTE with rivaroxaban in EINSTEIN-Jr phase II and III studies.

Trial registration

ClinicalTrials.gov number, NCT01145859; registration date: 17 June 2010.

     

To test or not: A registry-based observational study of an online decision support for prostate-specific antigen tests

BackgroundWatchful waiting is an essential part in the handling of patients with prostate cancer (PC). More effective disease management may be achieved by this strategy. Correct use of prostate-specific antigen (PSA) test is crucial and the general practitioner (GP) may therefore benefit from access to a clinical decision support system (CDSS) that focuses on this challenge. There are many barriers to the use of CDSSs. The aim of the present paper is to study if such barriers may be overcome by granting GPs easier access to a web-based CDSS via a hyperlink in the GPs’ electronic medical record system (EMR).MethodsIn the present population-based observational registry study with an intervention and control group, we created a web-based CDSS that was made accessible to GPs via hyperlink inserted into the EMR medical chart contents. The intervention was introduced 1 January 2011. Our outcome measure was the number of age-standardised PSA test rates per 1000 men per practice during three equally sized periods of 6 months within the study period from 1 January 2010 to 30 June 2011.ResultsWe found that none of the differences between intervention and control groups were statistically significant.ConclusionsProviding GPs with access to a CDSS to aid their decision to use the PSA, had no measurable effect on the GPs’ PSA testing behaviour.