An Unexpected Surge in Plasma BKPyV Viral Load Heralds the Development of BKPyV-Associated Metastatic Bladder Cancer in a Lung Transplant Recipient With BKPyV Nephropathy.

We report a lung transplant recipient who developed BK polyoma virus (BKPyV) DNAemia and BKPyV nephropathy. With careful management of his immunosuppression he achieved significant reduction in BKPyV DNAemia and stabilization of his kidney function. He later developed a high-grade bladder cancer and shortly thereafter he experienced a major upsurge in the level of BKPyV DNAemia that coincided with the discovery of hepatic metastasis. Retrospectively, the bladder cancer and the hepatic secondary tumor stained uniformly for SV40 large T antigen, and the BKPyV DNA sequences identified in plasma corresponded to BKPyV DNA within hepatic tissue, indicating that the spike in BKPyV load was likely derived from the circulating tumor cells or cell-free tumor DNA following metastases of a BKV-associated cancer. To the best of our knowledge, this is the first description of a surge in BKPyV load in a patient with controlled BKPyVN that heralded the appearance of a metastatic urothelial malignancy. This report discusses the literature on BKPyV-associated malignancies and the possibility that unexplained increases in BKPyV DNAemia may be a biomarker for metastatic BKPyV-related urothelial cancer.

Allele-specific cancer cell killing in vitro and in vivo targeting a single-nucleotide polymorphism in POLR2A.

Cancer is one of the diseases for which RNA interference is a potential therapeutic approach. Genes involved in the promotion or maintenance of tumor growth are obvious targets for RNAi. RNAi is also considered an attractive additional approach to conventional chemotherapy for cancer treatment. Moreover, siRNAs have shown a high specificity for their molecular target mRNAs as they can selectively inhibit cancer-promoting genes that differ by a point mutation. Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer cells and presents an absolute difference between normal and cancer cells. The regions of LOH are usually much larger than the tumor suppressor gene, which is lost, and has been shown to contain genes that are essential for cell survival. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. SNPs in essential genes that are frequently affected by LOH can be used as a target for a therapy against cancer cells with LOH. We have designed siRNAs against the gene of the large subunit of RNA polymerase II (POLR2A), a gene located in close proximity to the tumor suppressor gene p53, which frequently shows LOH in cancer cells. It is shown in vitro that siRNA can selectively inhibit POLR2A expression dependent on its genotype. Furthermore, cancer cell proliferation and tumor growth inhibition in nude mice was genotype dependent. We conclude that siRNA can be used for genotype-specific inhibition of tumor growth targeting an SNP in POLR2A in vivo.

[Botulinum toxin type A treatment of upper limb spasticity]. / Spastikbehandlung der oberen Extremität mit Botulinum Toxin Typ A.

In recent years, local injections with Botulinum toxin type A (BtxA) have become the treatment of choice for dystonia. However, several studies have demonstrated its efficacy and safety in the treatment of focal spasticity as well. These studies have shown efficacy and safety in upper limb spasticity treatment at a total dose between 500 and 1500 units of Dysport per injection session. While injections in upper arm muscles are easily administered without EMG-guidance, we recommend EMG-guidance for lower arm and finger muscles. In addition to functional improvement, BtxA treatment may also be considered for the following reasons: treatment of spasticity associated pain or painful muscle spasms, improved hygiene, facilitation of care, prevention of skin breakdown, and improved positioning of the upper limb. The definition of a realistic treatment goal, in agreement with the patient, as well as adjunctive physiotherapy are prerequisites for a successful BtxA treatment. Dose recommendations are given in Table 1.

Transcranial magnetic-evoked potentials under total intravenous anaesthesia and nitrous oxide.

Magnetic stimulation of the cortex and recording of the motor-evoked potentials (MEPs) by electromyography (EMG) is a well proven method to assess the descending pathways of the spinal cord and detect neurological impairment. We have assessed, in 33 adult patients undergoing spinal surgery, the influence of four total i.v. anaesthesia regimens (TIVA) on this recording technique. In 20 patients, the effect of 50% nitrous oxide was also studied. MEP amplitudes, latencies and success rates of stimulation were obtained in the steady-state after induction of anaesthesia. Combinations of midazolam and ketamine, and alfentanil and etomidate had the least effect on MEPs. Propofol (in combination with alfentanil or ketamine) showed marked depression of the MEP amplitude and the lowest success rates of stimulation. The latencies did not change at all. The addition of nitrous oxide significantly depressed the registered MEPs and lowered the success rates.

[Transcranial Doppler ultrasound: effects of intravenous anesthetics in neurosurgical patients]. / Transkranielle Dopplersonographie: Effekte intravenöser Anästhetika bei neurochirurgischen Patienten.

AIM: Although adverse effects on cerebral blood flow have been reported, intravenous anaesthetic and sedative agents are often used in neurosurgical patients. Monitoring of these effects by transcranial Doppler sonography remains a questionable procedure as long as the cross-sectional area of the insonated basal cerebral arteries is unknown. This study should evaluate the effects of thiopental, propofol, midazolam and alfentanil on flow velocities and "vessel cross-sectional area" (proportional to the reflected Doppler signal power) measured by transcranial Doppler sonography. METHOD: 19 patients with severe cerebral lesions (Glasgow Coma Scale < 6) were investigated. They were hyperventilated and sedated with fentanyl and flunitrazepam. The Doppler probe was fixed to the temporal bone and focussed to the middle cerebral artery of the more severely lesioned side. Baseline values of flow velocities and vascular cross-sectional area were measured. If routine nursing procedures required a deeper degree of sedation, either thiopental 2.5 mg/kg, propofol 1 mg/kg, midazolam 0.075 mg/kg or alfentanil 0.025 mg/kg were injected intravenously over 30 s. Further measurements were made 60, 120 and 300 s after start of the injection. Mean +/- SD were calculated, statistical evaluation was performed by analysis of variance and paired t-tests using the Bonferroni correction (p < 0.05). RESULTS: The injected agents induced significant decreases of the mean value of flow velocities; the "vessel cross-sectional area" remained unaltered. In some patients paradoxical increases of v were observed. CONCLUSION: The results indicate that intravenous anaesthetic agents are not likely to influence the cross-sectional area of the major basal cerebral arteries. Therefore TCD seems to be a valid tool to monitor the effects of these agents on the cerebral circulation of neurosurgical patients. This is probably of prognostic and therapeutic value.

Erythropoietin response to anaemia is not altered by surgery or recombinant human erythropoietin therapy.

Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) production and facilitate autologous blood donation before elective surgery. However, recent reports have suggested that surgery and/or EPO therapy may suppress endogenous erythropoietin secretion in response to anaemia. We therefore analysed the haemoglobin/erythropoietin relationship preoperatively and postoperatively in 71 autologous blood donors subjected to aggressive phlebotomy and six treatments with either EPO (150 U/kg, n = 16, 300 U/kg, n = 18, or 600 U/kg, n = 19) or placebo (n = 18). Using data from the three preoperative study visits, the linear relationship between log erythropoietin and haemoglobin was determined for each of the 18 placebo patients. We found no significant differences in the slopes of the relationships in this group during aggressive phlebotomy. Furthermore, there was no evidence of a significant difference in the erythropoietin level recorded postoperatively for each patient to that predicted from the patient's postoperative haemoglobin level, based on the haemoglobin/log erythropoietin relationship preoperatively. Similarly, for each of the EPO-treated groups, there was no evidence of a significant difference when comparing the recorded erythropoietin level to that predicted from each patient's postoperative haemoglobin level, based on the haemoglobin/log erythropoietin relationship preoperatively. We conclude that preoperative recombinant human erythropoietin therapy and/or surgery do not adversely affect the postoperative erythropoietin response to anaemia.

Transcranial Doppler sonography during isoflurane/N2O anaesthesia and surgery: flow velocity, "vessel area" and "volume flow".

Transcranial Doppler sonography (TCD) constitutes an advance in noninvasive monitoring of the cerebral circulation. However, as long as the diameter and cross-sectional area of the insonated middle cerebral artery (MCA) remain unknown, the derived flow velocities (v) are not informative. It is not known how the human MCA is influenced by anaesthetic agents. However, a TCD-modification allows noninvasive determination of "vessel area" (VA) and "volume flow" (VF) in MCA by analysing the backscattered Doppler power. This investigation evaluates the effects of isoflurane (in combination with N2O and surgery) on v, VA and VF. In 14 patients (ASA I) scheduled for minor surgical or gynaecological operations, anaesthesia was induced with droperidol, alfentanil, thiopentone and vecuronium. After intubation ventilation with N2O:O2 = 3:2 was adjusted, to maintain endexpiratory carbon dioxide (FECO2) constant between 4 and 5%. Baseline values of heart rate (HR), oscillometric mean arterial pressure (MAP), and TCD variables (v, VA VF) were measured before adding 2.4% isoflurane to the inspiratory mixture. Further measurements-were made 3, 6, 10, and 20 min after starting isoflurane. Surgery commenced between the sixth and tenth minute after isoflurane application. The MAP, FECO2, and v showed only minor alterations; HR increased after 6, 10 and 20 min. Transcranial "vessel area" and "volume flow" showed increases after isoflurane inhalation. The increase of "vessel area" supports the assumption that isoflurane greater than 1 MAC dilates large human cerebral arteries, so that if flow velocities are considered alone, alterations of cerebral blood flow may easily be underestimated.

A phase III trial of recombinant human erythropoietin therapy in nonanemic orthopedic patients subjected to aggressive removal of blood for autologous use: dose, response, toxicity, and efficacy.

BACKGROUND: Previous clinical trials have shown that the use of recombinant human erythropoietin (EPO) can facilitate autologous blood donation and reduce allogeneic blood transfusions in autologous blood donors who are anemic at first donation. However, the role of EPO therapy in nonanemic patients remains undefined. To identify this role, a randomized, controlled, multicenter dose-escalation trial was conducted in patients whose initial hematocrit was > 39 percent (0.39). STUDY DESIGN AND METHODS: EPO (150, 300, or 600 units/kg) or placebo was administered intravenously at each of six phlebotomy visits over a 3-week study period. Sixteen (14%) of 116 patients were unable to complete the treatment protocol because of adverse events (n = 11) or for personal reasons (n = 5); 2 patients (1 EPO and 1 placebo) experienced serious adverse events. RESULTS: In 91 evaluable patients, additional red cell production during the study period was 440 +/- 176, 621 +/- 215, 644 +/- 196, and 856 +/- 206 mL (mean +/- SD), respectively, for patients receiving placebo and EPO at 150, 300, and 600 units/kg (p < 0.05 for all EPO groups compared to placebo). However, the percentages of patients in each group who received allogeneic blood did not differ: 2 (9%) of 23 placebo patients and 6 (9%) of 68 EPO patients. CONCLUSION: It is concluded that, while EPO therapy increased preoperative red cell production, no clinical benefit could be demonstrated in autologous blood donors who were not anemic at first blood donation.

Effective use of a strategy using assigned red cell units to limit donor exposure for neonatal patients.

Critically ill neonatal infants receive frequent small-volume red cell (RBC) transfusions for replacement of blood drawn for laboratory analysis or for treatment of symptomatic anemia secondary to underlying medical conditions and/or a relative bleeding diathesis. Retrospective review of transfusion practice in a hospital revealed that the donor exposure-to-transfusion ratio was 1:1.3. In an effort to limit donor exposure and decrease the risk of transfusion-transmitted disease, a sterile connection device was used for multiple small-aliquot preparations. Three neonatal infants were given part of the same RBC unit, and the assigned RBC unit was used only until it reached 14 days of age. These criteria resulted in 49-percent reduction in donor exposure for neonatal infants weighting less than 1500 g and 27-percent reduction for those weighing more than 1500 g. The donor exposure-to-transfusion ratio decreased to 1:2.5. RBC waste from syringe aliquot preparation and residual volume at Day 15 were a mean of 32 percent of the total unit volume. Of 722 transfusion occurrences, there were no reported adverse effects due to elevated potassium subsequent to transfusion of 14-day-old RBCs. This limited-donor-exposure strategy effectively meets the needs of a transfusion service and will reduce the donor exposures of neonatal infants in similar institutions.

[Transcranial Doppler sonography and hemodynamics]. / Transkranielle Dopplersonographie und Hämodynamik.

13 patients without cerebral or cerebrovascular diseases were investigated by transcranial Doppler sonography during Swan-Ganz catheterisation for cardiologic purposes. Massive increases of mean arterial pressure, heart rate and cardiac index were observed during exercise; flow velocities in the middle cerebral artery increased only to the same extent as the endexpiratory carbon dioxide rose. However, the pulsatility index increased significantly (p less than 0.01) although a decrease should have been expected due to carbon dioxide accumulation. These results are indicative of a functioning autoregulation independent of carbon dioxide; they are relevant for interpretation of TCD results in patients with disturbed autoregulation.