Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In children, the 2 major RMS subtypes are alveolar and embryonal RMS. Aberrant Hedgehog/Patched1 (Hh/Ptch) signaling is a hallmark of embryonal RMS. We demonstrate that mice carrying a Ptch mutation in mesodermal Delta1-expressing cells develop embryonal-like RMS at a similar rate as mice harboring a Ptch mutation in the germline or the brachury-expressing mesoderm. The tumor incidence decreases dramatically when Ptch is mutated in Myf5- or Pax3-expressing cells. No RMS develop from Myogenin/Mef2c-expressing cells. This suggests that Hh/Ptch-associated RMS are derived from Delta1-positive, Myf5-negative, Myogenin-negative and Pax3-negative mesodermal progenitors that can undergo myogenic differentiation but lack stable lineage commitment. Additional preliminary genetic data and data on mesodermal progenitors further imply an interplay of Hh/Ptch and Delta/Notch signaling activity during RMS initiation. In contrast, Wnt signals supposedly suppress RMS formation because RMS multiplicity decreases after inactivation of the Wnt-inhibitor Wif1. Finally, our results strongly suggest that the tumor-initiating event determines the lineage of RMS origin.

Internet-based quality assurance registry for LDL apheresis QUASA--the apheresis registry.

Quality assurance measures have been demanded in the execution of extracorporeal LDL apheresis therapy (LDL apheresis) by the NUB-guidelines of the national committee of physicians and health insurance. The measures apply to specialist, organizational and mechanical requirements for the execution and billing of this method of treatment. Furthermore, as a result of the legal requirements of the SGB V, complementary BUB-guidelines were introduced in 1999. These should prove the therapeutic benefit of an LDL apheresis treatment. Beyond assuring quality of performance, documentation of the treatment is explicitly demanded. For the past two years, the non-profit QUASA gGmbH has developed a quality assurance registry for LDL apheresis based on those requirements. Since March 2003, the apheresis physicians can voluntarily take part in this registry through the internet. Beside the patient's medical history, data relevant to the treatment are also recorded. Because of the analysis of the national clinical data it will be possible for the first time, for the medical profession to fulfill the guidelines and ensure the quality of LDL apheresis.

Regional pelvic hyperthermia as an adjunct to chemotherapy (oxaliplatin, folinic acid, 5-fluorouracil) in pre-irradiated patients with locally recurrent rectal cancer: a pilot study.

The aim of this study was to evaluate the feasibility and toxicity of a novel hyperthermic chemotherapy approach for patients with locally recurrent adenocarcinoma of the rectum. All patients were pre-irradiated (> or = 45 Gy) and had histologically proven pelvic recurrence. Hyperthermic chemotherapy was applied according to a modified 'OFF'-schedule with weekly infusions of 43 mg/m2 of oxaliplatin (i.v., 120 min), 500 mg/m2 of folinic acid (i.v., 120 min) and 2.6 g/m2 of continuous infusional 5-fluorouracil (24 h) for 6 consecutive weeks. Oxaliplatin was started in parallel to pelvic radiofrequency hyperthermia that was provided by the BSD 2000-system. A total of 67 applications were administered to nine patients and were well tolerated. A total of 55/67 (82%) chemotherapy courses were applied without dose-reduction. In 62/67 (93%) hyperthermia sessions, a treatment time of > 60 min was maintained. Tolerated power levels were on average 600 W and, thus, slightly lower than those described in curative pelvic hyperthermia schedules. Eight out of 10 episodes of severe (WHO III degrees) toxicity represented typical side-effects of the chemotherapy given (nausea n = 4, diarrhoea n = 3, neuropathy n = 1). Two severe adverse events were firstly attributable to hyperthermia (haematuria, n = 1; deterioration of a decubital ulcer, n = 1). No patient suffered WHO-disease progression during the treatment period. Two patients achieved a partial remission. It is concluded that hyperthermic chemotherapy with oxaliplatin, folinic acid and 5-FU is feasible on an outpatient basis. Overall toxicity was moderate, although hyperthermia may add side-effects to this approach. Results, moreover, suggest a relevant palliative effect in patients with pre-irradiated pelvic recurrence of rectal cancer.

Whole-body hyperthermia in the scope of von Ardenne's systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer: a phase I/II study.

This phase I/II study evaluated the feasibility, toxicity and response rates of von Ardenne's systemic cancer multistep therapy (sCMT) when applied as an adjunct to cytostatic therapy in patients with metastatic colorectal cancer. sCMT consists of whole-body hyperthermia (WBH) at 41.8-42.1 degrees C, hyperglycaemia and hyperoxaemia. All patients who entered the trial first received three monthly courses of chemotherapy (folinic acid, 50 mg, days 1-5; 5-fluorouracil, 425 mg/m2, days 1-5; mitomycin 8 mg/m2, day 1), followed by response evaluation according World Health Organization (WHO) criteria. Responders (partial/complete remission) were assigned to three further courses of chemotherapy, whereas non-responders (stable/progressive disease) were allocated to additional sCMT on day 1 of every subsequent chemotherapy course. The WBH procedure was administered under general anaesthesia employing the Iratherm-2000 radiant heat device. Of 28 patients enrolled, 19 received more than three treatment courses. Eight of these 19 patients had responded to chemotherapy (PR) and thus obtained three further courses of chemotherapy alone. In 10 of 19 patients who had not responded (SD, PD), three additional courses of chemotherapy were combined with sCMT (with 25 sCMT applications). One patient who did not respond to initial treatment declined sCMT and was continued with chemotherapy alone. It was found that sCMT was feasible, but associated with a specific spectrum of grade III/IV toxicity (skin 20%, pain 16%, peripheral nerves 8% of treatment courses). The fact that three patients who did not respond to initial chemotherapy achieved a PR after additional sCMT suggests that sCMT may enhance the effect of chemotherapy in patients with colorectal cancer.

[QUASA-the apheresis registry]. / QUASA-Das Apherese-Register.

Quality saving measures are required at the execution of extracorporeal LDL apheresis therapy (LDL apheresis) by the NUB guidelines of the national committee of physicians and health insurance. The saving measures apply to specialist, organizational and apparatical conditions for execution and accounting of treatment methods. Furthermore, as a result of the lawful requirements of SGB V, complementary BUB guidelines were introduced in 1999. These ought to engage the therapeutic benefit of a LDL apheresis treatment. Beyond measures for quality assurance at execution a documentation of treatment is explicitly demanded. For two years now the non-profit Quasa gGmbH has been developed the quality assurance registry for LDL apheresis with the background of those requirements. Since March 2003 the apheresis physicians can voluntarily take part in the registry initiative by internet. Beside the clinical patient's medical history, treatment relevant data are recorded. Because of the analysis of the nationally ascertained clinical data, for the first time it will be possible for the medical profession to fulfill the guidelines of quality assurance for LDL apheresis. Moreover the treating apheresis physicians can establish an EDV-based individual patient documentation. All necessary measures of data protection and data security are in process on the technical and logistic realization of this registry initiative. An epidemiological data evaluation is regularly accomplished and the results are provided to the public.

Direct adsorption of low-density lipoprotein and lipoprotein(a) from whole blood: results of the first clinical long-term multicenter study using DALI apheresis.

Direct adsorption of lipoproteins (DALI) is the first low-density lipoprotein (LDL)-apheresis technique by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present study was performed to evaluate the efficacy, selectivity and safety of long-term DALI apheresis. Sixty-three hypercholesterolemic coronary patients were treated by weekly DALI sessions. Initial LDL-cholesterol (C) plasma levels averaged 238 +/- 87 mg/dl (range 130-681 mg/dl). On average, 34 sessions (1-45) were performed processing 1.5 patient blood volumes. The primary aim was to acutely reduce LDL-C by >or=60% per session. To this end, three different adsorber sizes could be employed, i.e., DALI 500, 750, and 1000, which were used in 4, 73, and 23% of the 2156 sessions, respectively. On average, 7387 ml of blood were processed in 116 min per session. This resulted in the following mean acute changes: LDL-C 198 --> 63 mg/dl (-69%), Lp(a) 86 --> 32 mg/dl (-64%), triglycerides 185 --> 136 mg/dl (-27%). HDL-C (-11%) and fibrinogen (-15%) were not significantly influenced. The mean long-term reduction of LDL-C was 42% compared to baseline while HDL-C slightly increased in the long run (+4%). The selectivity of LDL removal was good as recoveries of albumin, immunoglobulins, and other proteins exceeded 85%. Ninety-five percent of 2156 sessions were completely uneventful. The most frequent adverse effects were hypotension (1.2% of sessions) and paresthesia (1.1%), which were probably due to citrate anticoagulation. Access problems had to be overcome in 1.5%, adsorber and hardware problems in 0.5% of the sessions. In this multicenter long-term study, DALI apheresis proved to be an efficient, safe, and easy procedure for extracorporeal LDL and Lp(a) elimination.

Strong anomaly in diffusion generated by iterated maps.

We investigate the diffusion generated deterministically by periodic iterated maps that are defined by x(t+1) = x(t)+ax(z)(t)exp[-(b/x(t))(z-1)], z>1. It is shown that the obtained mean squared displacement grows asymptotically as sigma(2)(t) approximately ln (1/(z-1))(t) and that the corresponding propagator decays exponentially with the scaling variable |x|/square root of (sigma(2)(t))]. This strong diffusional anomaly stems from the anomalously broad distribution of waiting times in the corresponding random walk process and leads to a behavior obtained for diffusion in the presence of random local fields. A scaling approach is introduced which connects the explicit form of the maps to the mean squared displacement.

DALI apheresis in hyperlipidemic patients: biocompatibility, efficacy, and selectivity of direct adsorption of lipoproteins from whole blood.

Recently, the first apheresis technique for direct adsorption of low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] from whole blood (DALI) was developed that does not require a prior plasma separation. That markedly simplifies the extracorporeal circuit. The aim of the present study was to test the acute biocompatibility, efficacy, and selectivity of DALI apheresis. In a prospective clinical study, 6 hypercholesterolemic patients suffering from angiographically proven atherosclerosis were treated 4 times each by DALI. 1.3 patient blood volumes were treated per session at blood flow rates of 60-80 ml/min using 750 or 1,000 ml of polyacrylate/polyacrylamide adsorber gel. The anticoagulation consisted of an initial heparin bolus followed by a citrate infusion. The sessions were clinically essentially uneventful. Mean corrected reductions of lipoproteins amounted to 65% for LDL-cholesterol, 54% for Lp(a), 28% for triglycerides, 1% for HDL-cholesterol, and 8% for fibrinogen. The selectivity of lipoprotein removal was high. Cell counts remained virtually unchanged and no signs of hemolysis or clotting were detected. Cell activation parameters elastase, beta-thromboglobulin, interleukin-1beta, and IL-6 showed no significant increase. Complement activation was negligible. There was significant, but clinically asymptomatic, bradykinin activation in the adsorber with mean maxima of 12,000 pg/ml in the efferent line at 1,000 ml of treated blood volume. In conclusion, DALI proved to be safe, selective, and efficient for the adsorption of LDL-C and Lp(a), which simplifies substantially the extracorporeal therapy in hypercholesterolemic patients.

Sorting single events: mean arrival times of N random walkers.

Using a scaling approach we investigate the first passage time < mu(1,N)(r)> for the first out of N identical independently diffusing particles in ordered and disordered structures. For Euclidean spaces we obtain < mu(1,N)(r)> in terms of a series in (ln N)(-1), independent of dimension. In the case of disordered ramified fractals < mu(1,N)(r)> is expressed in terms of a series in (ln N)((1-d(l)(w))), where d(l)(w) describes how the mean topological distance evolves with time t. We propose a scaling behavior for the related quantity S(N)(t), the number of distinct sites visited by N particles. We verify our predictions by numerical simulations.

[Experimental studies of the precision of lamellar corneal sections]. / Experimentelle Untersuchungen zur Präzision lamellärer Hornhautschnitte.

Using an automatic rotating microkeratome for lamellar corneal grafting, 200 porcine corneal specimens were subjected to lamellar dissection. The aim of the study was to define the factors influencing the optimal thickness of the corneal lamella. The factors investigated were: the rotation speed of the trephine blade; the speed of blade advancement; the influence of lubrication fluids; intraocular pressure; geometry of the rotating blade. Ultrasound pachymetry was performed on non-fixed tissue in 13 defined positions. The optimal conditions for lamellar dissection with the rotating microkeratome were found to be a speed of 0.5 mm/s blade advancement, an intraocular pressure of 40 mmHg, lubrication of the cut area with a 0.05% Healon/BSS +/- solution. Under these conditions the thickness of the lenticule showed an inhomogenity of 2.5% total thickness, which was located in the direction of blade advancement and blade rotation speed.

Effects of DDT and dieldrin on intestinal glucose transport and brush border hydrolases. A comparison with phenobarbital and methylcholanthrene.

The enhancement of in vitro small intestinal transcellular glucose transport in NMRI mice after oral administration of the organic pesticides 2,4-DDT and dieldrin can be shown to be due to an increased active transport at the site of the brush border membrane. Intestinal disaccharidase activities were concomitantly elevated in the dieldrin group, while DDT produced no effects with intestinal hydrolases. The classic enzyme inducing agents phenobarbital and methylcholanthrene failed to stimulate intestinal glucose transport, although both increased intestinal disaccharidase activities considerably, thus questioning a close relation between these digestive and absorptive functions in the translocation of glucose. Intestinal alkaline phospatase activity was enhanced after DDT, dieldrin and methylcholanthrene treatment, but not with phenobarbital. It is suggested that DDT and dieldrin exert their stimulating effect on intestinal glucose transport by a mechanism different from general induction of metabolic pathways.

Effects of lavage techniques with third molar surgery.

A comparison study of 206 mandibular third-molar surgical sites, half of which were irrigated with high volumes of isotonic normal saline solution with a conventional hand syringe and half of which were irrigated with high volumes of isotonic normal saline solution by means of a mechanical pulsating lavage instrument, revealed the following: 1. No cases of localized osteitis occurred with the use of mechanical irrigation in 103 surgical sites (0%). 2. One case of localized osteitis occurred with regular irrigation in 103 surgical sites (0.97%). 3. The over-all incidence of localized osteitis was one case in 206 surgical sites (0.49%). 4. One case of infection occurred with mechanical lavage (0.97%). 5. Two cases of infection occurred with conventional lavage (1.96%). 6. The over-all incidence of infection was three cases in 206 surgical sites (1.45%). 7. No significant differences occurred at the 0.95 level of confidence when the two groups' 3- and 5-day healing were compared. 8. A fairly even distribution of postoperative infections and/or localized osteitis was noted among the cases handled by the three surgeons directly involved in the performance of the operations. 9. Three hundred fifty milliliters of isotonic normal saline solution under pressure (whether electrical or conventional) appreciably reduced the reported incidence of localized osteitis without the use of antibiotics. 10. The mechanical irrigator was less cumbersome and faster (30 seconds for 350 ml.) than the conventional hand syringe (4 to 5 minutes for 350 ml.). 11. The sterilization procedure was more complicated for the mechanical irrigator (gas autoclave) than for the conventional hand syringe (presterilized disposable type). 12. Loose (unattached) soft tissue and bony spicules were thoroughly removed by 350 ml. of irrigation.