Computer-assisted diabetes therapy--a challenge for modern medicine

By the use of computers in the therapy of diabetes new diagnostic and therapeutic possibilities are brought about. The computers open the possibility for a comprehensive data seizing, evaluation of the stored material and possibilities of various abilities for demonstration. Moreover, it becomes possible to regulate the therapy more subtly with the help of self-adapting programs and in its consequence to render it more effective than the own management of therapy is able to do it. This manifests itself significantly in badly or only moderately stabilised diabetics. In very well educated and trained diabetics even the superiority of the management of the computer becomes visible. Here this can no more be shown in the improvement of the stabilisation of diabetes which can no more be improved without risks for the patient. In these patients it is the reduction of the frequency of hyperglycaemia, by means of which can be shown that the stabilisation of diabetes in diabetics who were well stabilised already before can still be improved by the computer therapy. In addition to this the computer seems to cause further positive effects on the learning behaviour of the diabetics.     

Signal transduction by the platelet Fc receptor

We have evaluated the mechanism by which crosslinking human platelet Fc receptor (FcR) for IgG triggers platelet aggregation and the platelet release reaction. Platelet FcR was crosslinked by incubating purified human platelets with anti-FcRII monoclonal antibody and F(ab')2 anti- mouse Ig. The resultant [Ca2+]i increase, monitored by Fura-2 and measured in the absence of extracellular Ca2+, reached a peak of 750 +/- 50 nmol/L. The effects of cyclooxygenase inhibitors, aspirin and indomethacin, and a phospholipase A2 inhibitor, dibromoacetophenone, were examined. Regardless of the inhibitor, at least 25% of the [Ca2+]i increase remained. Thrombin (0.2 U/mL) stimulated an immediate [Ca2+]i increase that reached 1.95 +/- 0.8 mumol/L. The [Ca2+]i increase generated by thrombin was only slightly reduced by these inhibitors. Crosslinking the FcRII of platelets resulted in a fivefold increase in the production of [3H]inositol phosphates, (IP) which, in the absence of extracellular Ca2+ was insensitive to aspirin. The activation of a [Ca2+]i increase along with the measured increases in IP indicate that FcRII crosslinking leads to the activation of phospholipase C (PLC). In contrast to thrombin, platelet activation via FcRII depends to a large extent on arachidonic acid metabolites. However, neither cyclooxygenase nor phospholipase A2 inhibitors completely blocked FcRII-stimulated [Ca2+]i increase. These observations led us to propose that crosslinking of platelet FcRII initially activates PLC.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

The management of trauma victims with head injury: a study by the national confidential enquiry into patient outcome and death

Introduction

In 2006 the National Confidential Enquiry into Patient Outcome and Death undertook a large prospective study of trauma care, which revealed several findings pertaining to the management of head injuries in a sample of 493 patients.

Methods

Case note data were collected for all trauma patients admitted to all hospitals accepting emergencies in England, Wales, Northern Ireland and the Channel Islands over a three-month period. Severely injured patients with an injury severity score (ISS) of ≥16 were included in the study. The case notes for these patients were peer reviewed by a multidisciplinary group of clinicians, who rated the overall level of care the patient received.

Results

Of the 795 patients who met the inclusion criteria for the study, 493 were admitted with a head injury. Room for improvement in the level of care was found in a substantial number of patients (265/493). Good practice was found to be highest in high volume centres. The overall head injury management was found to be satisfactory in 84% of cases (319/381).

Conclusions

This study has shown that care for trauma patients with head injury is frequently rated as less than good and suggests potential long-term remedies for the problem, including a reconfiguration of trauma services and better provision of neurocritical care facilities.     

The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury

1. Download high-res image (341KB)
2. Download full-size image

     

Recent strategies for the use of paclitaxel in the treatment of urological malignancies

Paclitaxel, a natural anticancer drug, has gained widespread acceptance as an active broad-spectrum antitumor agent, including its use in urological malignancies, particularly urothelial tract cancer and testicular cancer. The mechanism of action, based on the premature stabilization of the microtubule assembly with disruption of the cytoskeletal framework, is completely different from those of DNA-damaging agents, e.g., cisplatin and ifosfamide. As a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer, with an overall response rate of 40–50% being obtained in previously untreated patients. These promising single-agent results have prompted the use of combination regimens including, in particular, cisplatin and paclitaxel. A high degree of activity for the cisplatin-paclitaxel combination as reflected by responses in 50–80% of patients, including a substantial number of complete responses (>30%), has been identified. The role of other agents such as vinorelbine, methotrexate, 5-fluorouracil, or ifosfamide as additions to this two-drug combination currently remains open. The combination of paclitaxel plus ifosfamide or vinorelbine in the absence of a platinum derivative has yielded rather disappointing results. Of particular interest may be the combination of paclitaxel and carboplatin. Both drugs can be given to patients with impaired renal function. Overall response rates of 45–60% have been reported in phase II studies. The so-called platelet-sparing effect of paclitaxel given in combination with carboplatin has resulted in a surprisingly low frequency of myelotoxicity, particularly thrombocytopenia. The combination of paclitaxel with carboplatin is being compared in an ongoing trial against the current standard MVAC regimen (methotrexate/vinblastine/Adriamycin/cisplatin) in patients with metastatic disease. Furthermore, the activity of paclitaxel-based combinations is currently being explored in the neoadjuvant setting in phase II studies, and the potential for the combination with the other new promising agent – gemcitabine – will be evalutated in a phase I setting. In prostate cancer, estramustine phosphate is widely used as palliative treatment for patients with hormone-refractory disease. In vitro synergistic activity has been observed between estramustine and paclitaxel in prostate-cancer cell lines, although paclitaxel has not demonstrated single-agent activity in patients with hormone-refractory prostate cancer. In clinical trials the combination of the two agents was associated with increased gastrointestinal toxicity. The addition of etoposide as a third drug has yielded prostate-specific antigen (PSA)-response rates of >50%, but data on quality of life and survival time have not been reported for these combinations. A true clinical role for paclitaxel in prostate cancer has therefore not been established. Paclitaxel has finally demonstrated single-agent activity in relapsed and/or cisplatin-refractory testicular cancer in recent phase II trials, indicating different mechanisms of resistance to cisplatin and paclitaxel. These results have formed the rationale for the introduction of paclitaxel as part of combination chemotherapy regimens in patients with relapsed but chemosensitive testicular cancer. Preliminary results demonstrate that paclitaxel can be safely included into these conventional-dose combination regimens. When it is used prior to high-dose chemotherapy, sufficient numbers of peripheral blood stem cells (PBSCs) for high-dose therapy can be collected. The final role of paclitaxel in risk-adapted chemotherapeutic strategies in testicular cancer is not defined, but it appears that paclitaxel-based combinations can achieve a substantial response rate in patients with relapsed disease.     

Anxiolytic-like activity of the non-selective galanin receptor agonist, galnon

Galanin's influence on monoaminergic neurotransmission, together with its discrete CNS distribution in corticolimbic brain areas, points to a potential role for this neuropeptide in mediating anxiety- and depression-like responses. To evaluate this hypothesis, the non-selective galanin receptor agonist, galnon, was tested in multiple preclinical models of anxiolytic- and antidepressive-like activity. Acute administration of galnon (0.03-1mg/kg, i.p.) dose-dependently increased punished crossings in the four plate test, with magnitude similar to the effects of the endogenous ligand, galanin (0.1-1.0 microg, i.c.v.). Moreover, the effects of galnon and galanin were blocked by central administration of the non-selective galanin receptor antagonist, M35 (10 microg, i.c.v.). Interestingly, the benzodiazepine receptor antagonist, flumazenil (1mg/kg, i.p.), reversed galnon's effect in the four plate test, implicating GABAergic neurotransmission as a potential mechanism underlying this anxiolytic-like response. In the elevated zero maze, galnon (0.3-3.0mg/kg, i.p.) and galanin (0.03-0.3 microg, i.c.v.) increased the time spent in the open arms, while in the stress-induced hyperthermia model, galnon (0.3-30 mg/kg, i.p.) attenuated stress-induced changes in body temperature. Consistent with these anxiolytic-like effects, in vivo microdialysis showed that acute galnon (3mg/kg, i.p.) treatment preferentially elevated levels of GABA in the rat amygdala, a brain area linked to fear and anxiety behaviors. In contrast to the effects in anxiety models, neither galnon (1-5.6 mg/kg, i.p.) nor galanin (0.3-3.0 microg, i.c.v.) demonstrated antidepressant-like effects in the mouse tail suspension test. Galnon (1-10mg/kg, i.p.) also failed to reduce immobility time in the rat forced swim test. In vitro, galnon and galanin showed affinity for human galanin receptors expressed in Bowes melanoma cells (K(i)=5.5 microM and 0.2 nM, respectively). Galanin displayed high affinity and functional potency for membranes expressing rat GALR1 receptors (K(i)=0.85 nM; EC(50)=0.6 nM), while galnon (10 microM) failed to displace radiolabeled galanin or inhibit cAMP production in the same GALR1 cell line. Galnon (10 microM) showed affinity for NPY1, NK2, M5, and somatostatin receptors but no affinity for galanin receptors expressed in rat hippocampal membranes. Taken together, the present series of studies demonstrate novel effects of galnon in various preclinical models of anxiety and highlight the galaninergic system as a novel therapeutic target for the treatment of anxiety-related disorders. Moreover, these data indicate rodent GALR1 receptors do not mediate galnon's in vivo activity.