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In recent decades, meltwater runoff has accelerated to become the dominant mechanism for mass loss in the Greenland ice sheet1-3. In Greenland's high-elevation interior, porous snow and firn accumulate; these can absorb surface meltwater and inhibit runoff4, but this buffering effect is limited if enough water refreezes near the surface to restrict percolation5,6. However, the influence of refreezing on runoff from Greenland remains largely unquantified. Here we use firn cores, radar observations and regional climate models to show that recent increases in meltwater have resulted in the formation of metres-thick, low-permeability 'ice slabs' that have expanded the Greenland ice sheet's total runoff area by 26 ± 3 per cent since 2001. Although runoff from the top of ice slabs has added less than one millimetre to global sea-level rise so far, this contribution will grow substantially as ice slabs expand inland in a warming climate. Runoff over ice slabs is set to contribute 7 to 33 millimetres and 17 to 74 millimetres to global sea-level rise by 2100 under moderate- and high-emissions scenarios, respectively-approximately double the estimated runoff from Greenland's high-elevation interior, as predicted by surface mass balance models without ice slabs. Ice slabs will have an important role in enhancing surface meltwater feedback processes, fundamentally altering the ice sheet's present and future hydrology.

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Laser acupuncture is a painless, non-invasive, and cost effective treatment for children with therapy resistant monosymptomatic nocturnal enuresis. This kind of acupuncture is an alternative treatment with positive results. Currently, we are treating 24 children (22 males, 2 females) out of a planned 200 children aged between 5 and 12 years. These patients have had a classic monosymptomatic nocturnal enuresis. Up to now, school medicine therapy has been unsuccessful. Over 3 months, we treated the children once a week with acupuncture, inserting at the following points: medial Ren 3, bilateral Ma 36, bilateral Mi 6, bilateral Bl 33, medial Ren 6, medial Ex B5.A better enuresis frequency was achieved in 21 out of the 24 children (87.5%). Before the end of the 12th treatment, six of the 24 children (25%) were completely dry and 16 (66.6%) had an enuresis frequency reduced by more than half after the 12th treatment.

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In a prospective study, from September 2000 to September 2001, all ureteroscopies ( n=140) were performed under local and intravenous patient controlled analgesia using continuous infusion of remifentanil (Ultiva). The dosage of 0.15 micro g/kg/min was adapted to changing intraoperative pain (range 0.08-0.30 micro g/kg/min). Preoperative sedation with midazolam 2 mg was given 5 min prior to ureteroscopy. The efficacy of monitored anesthesia care ("Big MAC") was quantified by the patient using a visual analogue pain scale. A total of 97.1% (136/140) of the procedures were performed and finished under remifentanil. Only four male patients underwent conversion to general anesthesia due to insufficient analgesia. All but one patient would choose remifentanil again for first line anesthesia. Significant differences in pain scale values were noticed for male/female patients and ureteroscopies above/below the iliac vessel crossing. Side effects were rare being mainly hypoxic events (pO(2)<90% in 5.1%). Indication, intraoperative procedure, average surgery time (24 min), complications and primary success rate (96.6/90/63.3% stone free for distal/mid/proximal ureter, respectively) did not differ from the control group under general anesthesia. Ureteroscopies with remifentanil are safe, universally applicable because of refifentanil's organ independent esterase metabolism and as effective as general anesthesia. There is no need for PACU stay for patients due to the ultra-short drug half-life, and therefore remifentanil is cost effective and perfect in an outpatient setting.

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Acute urinary retention in children may be associated with a broad spectrum of different causes. Acute appendicitis or acute ovarian torsion are rare and complicate the diagnosis. The case of a 6-year-old girl with urinary retention caused by ovarian torsion is reported, in which clinical presentation showed nonspecific complaints and ultrasound demonstrated a retrovesical mass. The long-standing ovarian torsion could only be diagnosed by laparotomy. This case once again demonstrates possible difficulties in obtaining a correct diagnosis, especially when imaging techniques reach their limits. Here, the anatomical structures had become so altered by adhesions of the omentum that they were no longer identifiable, rendering the advantageous, non-invasive laparoscopy ineffective. As a result, laparotomy became the most accurate and reliable method for obtaining a correct diagnosis. The occurrence of acute urinary retention with ovarian torsion can be explained by an earlier disturbance of the vegetative nervous system.

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PURPOSE: We evaluated the results and complications of children with reflux treated with the Politano-Leadbetter ureteroneocystostomy. In particular, we evaluated pre- and postoperative renal parenchymal scarring and the late development of hypertension. MATERIALS AND METHODS: From 1965 through 1996, 666 children (814 renal units) were reimplanted by nine urologists. The average postoperative evaluation was 10.3 years, and 68.8% of all patiens were evaluable 10 years after surgery. RESULTS: Postoperative complications occurred in 7.8% and consisted of small bowel serosal injury (0.3%), vesicocutaneous fistula (0.4%) and retrovesical hematoma (0.3%). Persistent reflux was the most common postoperative complication (5.6%) and was found to occur in higher grades of vesicorenal reflux. Ureteral stricture and hydronephrosis were seen in 1.2% of children, and was corrected with a secondary reimplantation. Late stricture occurred in all but 1 patient (0.2%). Renal parenchymal scarring was found in 21.2% of patients preoperatively, and this increased over time postoperatively to 27.7%. In 8.7% of these patients, hypertension developed between the 6th and 17th postoperative year. In 6.1%, nephrectomy was carried out, which normalized blood pressures in 87. 9% of these 30 patients. CONCLUSIONS: The Politano-Leadbetter ureteroneocystostomy was successful in 93.6% of all 814 renal units surgically treated. The operation is safe, but can be associated with late development of hypertension despite correction of the reflux.

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Three novel alkylphospholipid and four novel O-alkylglycerophospholipid derivatives of fludarabine (F-ara-AMP), known as a drug for the clinical treatment of chronic lymphocytic leukemia, were synthesized. The antiproliferative activity was determined in comparison to the parent nucleoside fludarabine in an immortalized but nontumorigenic human mammary epithelial cell line (H 184 A1N4), in two human breast tumor cell lines (MaTu and MCF7), and in two leukemic cell lines (HL 60 and Daudi). Fludarabine inhibited the growth of the leucemic cell lines very effectively. The breast tumor cell lines responded with much less sensitivity. The antiproliferative potency of the new compounds strongly depended on the chemical structure of the lipid component, and derivatives with a high effectiveness against one or both of the breast tumor cell lines were described.

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PURPOSE: Prepubic urethrectomy is a simple, safe alternative to perineal urethrectomy. The lithotomy position can be avoided and, thus, operative time and risk of deep venous thrombosis are decreased. We developed a simple modification because of difficulty in dissecting the bulbous urethra. MATERIALS AND METHODS: From 1996 through 1998 prepubic urethrectomy was performed using a modified procedure in 21 patients with invasive bladder carcinoma undergoing radical cystectomy and supravesical diversion. After periurethral mobilization the urethra was cannulated with an 18F catheter, sutured distal and stripped free. RESULTS: Operative time decreased to 20 to 30 minutes with no significant postoperative complications. CONCLUSIONS: Our modification of prepubic urethrectomy is safe, fast and easy.

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The ability of four different antitumor phospholipids, 1-O-hexadecyl-2-chloro-2-deoxyglycero-3-phosphocholine (ET16CIPC), hexadecylphosphocholine (C16OPC), hexadecylphospho-L-serine analogs (C16OPS, C16OPS-N-Ac) and cytidine-5'-hexadecylphosphonophosphate (C16PCMP) to modulate the cytosolic Ca2+ concentration [Ca2+]i was studied in an immortalized human mammary epithelial cell line H184 A1N4. The compounds induced different modes of activity depending on their structure and concentration. ET16CIPC induced between 0.31 and 5 microM a concentration dependent transient increase which was followed by a sustained increase at 10 microM. Studies using LaCl3 and Mn2+ quench of the Fura-2 fluorescence indicated that both effects are the result of an extracellular Ca2+ influx. Low concentrations of C16OPC, C16OPS and C16OPS-N-Ac induced no, or only a small, transient increase, whereas C16PCMP caused a decrease in [Ca2+]i. Thapsigargin and cyclopiazonic acid, specific inhibitors of the endoplasmic reticulum Ca(2+)-ATPase, prolonged the transient [Ca2+]i increase following ET16CIPC concentration dependently, increased markedly the small transient increase following C16OPC and the C16-phosphoserine analogs and converted the decrease in the basal [Ca2+]i level induced by C16PCMP to an increase. The identical effects with thapsigargin and cyclopiazonic acid provide evidence that the [Ca2+]i response observed is an expression of the balance between the ability of an analog to raise [Ca2+]i and to remove Ca2+ by activation of the endoplasmic reticulum Ca(2+)-ATPase. This behaviour might contribute to the antiproliferative effectiveness of antitumor phospholipids.

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ara-Cytidine-5'-alkylphosphonophosphates and the corresponding -diphosphates were found to be cytostatically active in vitro against the human mammary epithelial cell line H184 A1N4 and the human mammary tumor cell line MaTu. Our results indicate that the replacement of the diphosphate by the phosphonophosphate group has no influence on antiproliferative activity in this case. The compounds were more active than the corresponding cytidine phospholipid conjugates and related compounds lacking a cytostatically active nucleoside, the ara-C prodrug Cytoros, and were slightly less active than ara-C. The cytostatic effect was prevented by 2'-deoxycytidine indicating their action as prodrugs of ara-C. In contrast to ara-C, they increase [Ca2+]1 in H184 A1N4 cells, pointing to a different mechanism of action in addition to their prodrug effect. In combination with phospholipid analogs, synergistic effects could be observed. Further studies within the disease-oriented in vitro Anticancer Screening Program of the National Cancer Institute show selectivity for certain cancer cell lines. The hexadecyl derivatives revealed a significant antitumor activity in vivo against the murine lymphatic leukemia P 388 cells being equally potent or even superior to ara-C. In contrast to ara-C, they were found to be orally active. Side effects measured as leukopenia and body weight reduction were less pronounced than with the parent drug.

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Recent studies have shown that phosphono analogs of cytidine-5'-diphosphate diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety exhibit antiproliferative activity in vitro. As an extension of our previous work we tried to elucidate whether the presence of the cytidine component is necessary for cytostatic activity. In this context we have synthesized similarly structured nucleoside-phospholipid conjugates containing nucleoside components other than cytidine, which also do not exhibit cytostatic properties as such. The compounds include 5'-alkyldiphosphates and 5'-alkylphosphonophosphates of 2'-deoxycytidine, thymidine and adenosine with different alkyl chain length as well as selected 3-hexadecyl-2-chloro-2-deoxyglycero-(1)-diphosphates and -phosphonophosphates of these nucleosides. The chemical structures of the newly synthesized nucleoside-phospholipid conjugates were confirmed by fast atom bombardment (FAB) and electrospray ionization (ESI) mass spectrometry. It was found that these compounds also inhibit the cell growth of different human cell lines, i.e. the presence of the cytidine component is not a necessary prerequisite for the antiproliferative activity of these nucleoside-phospholipid conjugates.

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Antiproliferative alkyllysophospholipid (ALP) analogs produced multiple effects on the cytosolic Ca++ concentration ([Ca++]i) in an immortalized human breast epithelial cell line (H 184). The addition of small concentrations resulted in a short transient [Ca++]i response. With higher concentrations the transient rise was followed by a sustained increase. Pretreatment of cells with the ALP analogs for two minutes inhibited the transient [Ca++] response. Increases in [Ca++]i and inhibition of the transient increase were studied in relation to the dose and structure of several ALP analogs. In a series of alkylphospho-L-serine analogs with different lengths of the alkyl chain we found different dependencies of the stimulatory and inhibitory effects on the dose and the structure. The ability to increase [Ca++]i is absent with the C14 and C15 analogs, is low with the C16 and high with the C18 analog. With the exception of the C12 analog, a dose-related inhibition was observed with all derivatives but the effective concentrations differed very strongly and the maximal potency was reached with the C15 and C16 analogs. The antiproliferative action seems to correlate rather with the potency to inhibit the transient [Ca++]i response than with its stimulation.

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The chemical synthesis of cytidine-5'-alkyl- and cytidine-5'-alkyl (acyl)deoxyglycerophosphonophosphates is reported. The compounds obtained represent a novel class of cytostatically active agents based on phospholipids, which inhibit the growth of various tumor cell lines in vitro. They are phosphono analogs of the cytidine-5'-diphosphate-diacylglycerol (CDP-DAG) possessing a structurally modified lipid moiety and a phospholipase C-resistant P-C bond. The antiproliferative efficacy of the cytidine-5'-alkylphosphonophosphates strongly depends on the alkyl chain length. The cytidine-5'-hexadecylphosphonophosphate was found to be the most effective compound tested in this study. Its cytostatic effect was distinctly higher than that of the alkyl(acyl) deoxyglycero derivatives and of the corresponding diphosphates. The structure of the new compounds were confirmed by fast atom bombardment mass spectrometry (FAB). The FAB fragmentation pattern is discussed.

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The influence of cytostatically active alkyllysophospholipid analogs with different chemical structure on IP3 (inositol-1,4,5-trisphosphate) formation and intracellular Ca++ concentration was studied in human mammary epithelial cells before and after transfection with v-erb B oncogene DNA. Transformed cells showed an increased IP3 formation compared with normal cells. In the presence of ALP (alkyllysophospholipid) analogs IP3 formation is inhibited more strongly in transformed cells than in normal cells, dependent on the structure of ALP analogs. Furthermore, these compounds increased [Ca++]i (intracellular Ca++ concentration) in transformed cells much more strongly than in normal cells. From these results, obtained in pursuit of an oncogene-related cancer treatment, it follows that ALP analogs may inhibit processes in signal transduction in cells more strongly after transfection with a defined oncogene than before.

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Synthetic alkyl-lysophospholipids (ALP) are a new class of antitumor agents which interact with the cell membrane and the intracellular signal transduction at several sites. We studied the modulation of the intracellular calcium concentration ([Ca++]i) induced by two alkylglycerophosphocholines as well as hexadecylphosphocholine and hexadecylphosphoserine in a nontumorigenic and in a tumorigenic breast cell line. We found three distinct [Ca++]i-modulating effects: a transient increase, a decrease and a sustained increase. Their relative contribution to the observed response varies with different cell types, with the proliferation state, with the structure and with the concentration of the ALP analogs. The transient as well as the sustained increase in [Ca++]i depend mainly on extracellular Ca++; however, the Ca++ influx-inducing pathways might be different. The multiple [Ca++]i-increasing and decreasing effects induced by ALP analogs are discussed in relation to their influence on numerous Ca(++)-dependent effects, e.g. proliferation, differentiation, apoptosis and cytotoxicity.

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Previous investigations in human precancerous and cancerous tissues identified subsets of cells that were different in respect to a heparin-induced increase in fluorescence intensity (IFI) monitored by flow cytometry. We suggested that differences in IFI were due to different chromatin types in the cells and related to different transcriptional capacities. This study is to prove our suggestion. Heparin-induced IFI was measured in the human breast cell line H184A1N4 cultured under different, defined growth conditions. Cells in quiescence obtained from a culture deprived of serum and other supplements essential for growth or from the confluent state revealed a higher IFI than cells restimulated to proliferation by addition of complete medium; here a reduced IFI was found. Changes in the magnitude of heparin-induced IFI precede changes in cell-cycle stage distribution by at least 6.5 h. We conclude that the heparin-induced effects, as revealed by flow cytometry, reflect changes in the accessibility of chromatin to transcription in different stages of proliferative activity. The results confirm our conclusions from previous findings with clinical material.

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3'-Deoxy-3'-fluorothymidine (FT), at a concentration of 30 muM, is capable of inducing about 50% of human myeloid K562 cells to differentiate while reducing the growth potential (clonogenicity, growth rate) approximately by one half. For comparison, arabinosylcytosine (Ara C), at 0.1 muM, causes the same percentage of differentiation, but cell proliferation is abolished by >80%. Induction of differentiation is more correlated with the inducer concentration than with incubation periods for both agents. After removal of FT after 5 days of treatment, the cells resume normal growth for the next 5 days. The absolute number of differentiated cells increases within this period. In accordance with their effect on the growth potential, the shift of the colony/cluster ratio towards higher numbers of clusters is greater for Ara C than for FT. Cells treated with either compound are larger than control cells. While in control colonies only very few differentiated cells are found by microscopic inspection, up to 50% of FT treated colony cells are estimated as differentiated. In many clusters and small colonies of Ara C treated cells more than 80% of the cells are benzidine-positive. Loss of clonogenicity of CFU-GM from mouse bone marrow is stronger with Ara C treatment in liquid cell culture for 2 days than with FT treatment in the same concentration range.

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Net joint moments are often used to quantify the loading of structures (e.g. the intervertebral disc at L5S1) during lifting. This quantification method is also used to evaluate the loading of the knee, for instance, to determine the effect of backlifting as opposed to leglifting. However, the true loading of the joint as derived from net joint moments can be obscured by a possible co-contraction of antagonists. To unravel the mechanisms that determine the net joint moments in the knee, the leglift was compared to the backlift. Although a completely different net knee moment curve was found when comparing the two lifting techniques, it appeared to be closely related to the ground reaction force vector and its orientation with respect to the joint centre of rotation (R > 0.995). This close relation was established by co-contraction of both flexors and extensors of the knee. Furthermore, a close relation appeared to exist between the joint moment difference between hip and knee and the activity difference between rectus femoris muscle and hamstring (R = 0.72 and 0.83 in leglift and backlift, respectively). The knee-ankle joint moment difference and the activity of the gastrocnemius showed a close relation as well (R = -0.89 and 0.96 in leglift and backlift, respectively). These relations can be interpreted as a mechanism to distribute net moments across joints. It is concluded that during lifting tasks the intermuscular coordination is aimed at coupling of joint moments, such that the ground reaction force points in a direction that provides balance during the movement. The use of net joint moments as direct indicators for joint loading (e.g. knee) seems, therefore, questionable.

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Phospholipid analogues were studied with regard to their cytostatic activity on different tumour cell lines and on murine bone marrow cells. Compounds compared for their activity were alkylglycero- and alkyl-phosphocholines with the corresponding serines and the alkylphosphocholines and -serines with the corresponding phosphono derivatives. Moreover, compounds containing cytidine 5'-diphosphate instead of the phospho (or phosphono-) choline or serine moiety were studied. rac-2-Chloro-2-deoxy-2-deoxy-1-0-hexadecyl-glycero-3-phosphocholine (cpd. Id), hexadecylphosphocholine (cpd. Ia) as well as hexadecylphosphonocholine (cpd. Ib) inhibited growth of tumour cells in suspension and monolayer culture and their colony and cluster formation in agar culture but not that of bone marrow cells. The exchange of choline for serine in these compounds results in the loss of this type of antitumour specificity. However, dodecylphospho-L-serine (cpd. IIc) is as specific as the choline derivatives Ia, b, d mentioned. Thus, for serine compounds the specificity for tumour cells might depend in a critical way on the length of the alkyl chain. The phosphono compounds Ib, IIb show almost the same activity as the corresponding compounds hexadecylphosphocholine (cpd. Ia) or hexadecylphosphoserine (cpd. IIa). The CDP-derivatives (IIIa, d, e, f) inhibited growth of tumour cells in suspension or monolayer cultures but not the colony and cluster formation in agar (i.e. they do not decrease the plating efficiency) from either tumour or bone marrow cells.

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