Posttraumatic hypothermia reduces polymorphonuclear leukocyte accumulation following spinal cord injury in rats

The present study addresses the effects of moderate posttraumatic hypothermia (32 degrees C) on the temporal and regional profile of polymorphonuclear leukocyte (PMNL) accumulation after traumatic spinal cord injury (SCI). We hypothesized that posttraumatic hypothermia would reduce the degree of inflammation by reducing PMNL infiltration. Rats underwent moderate spinal cord injury at T10 using the NYU impactor device. In the first study, the temporal profile of myeloperoxidase (MPO) activity (a marker of neutrophil accumulation) under normothermic (37 degrees C) conditions was determined. The animals were allowed to survive for 3 or 24 h, or 3 or 7 days after SCI. Spinal cords were dissected into five segments rostral and caudal to the injury site. Additional animals were studied for the immunocytochemical visualization of MPO. In the second study, rats were sacrificed at 24 h after a monitoring period of normothermia (36.5 degrees C/3 h) or hypothermia (32.4 degrees C/3 h) with their controls. In the time course studies, MPO enzymatic activity was significantly increased at 3 and 24 h within the traumatized T10 segment compared to controls. MPO activity was also increased at 3 h within the rostral T8 and T9 segments and caudal T11 and T12 segments compared to controls. At 24 h after trauma, MPO activity remained elevated within both the rostral and caudal segments compared to control. By 3 days, the levels of MPO activity were reduced compared to the 24-h values but remained significantly different from control. Neutrophils that exhibited MPO immunoreactivity were seen at 6 and 24 h, with a higher number at 3 days. PMNLs were located within the white and gray matter of the lesion and both rostral and caudal to the injury site. Posttraumatic hypothermia reduced MPO activity at 24 h in the injured spinal cord segment, compared to normothermic values. The results of this study indicate that a potential mechanism by which hypothermia improves outcome following SCI is by attenuating posttraumatic inflammation.     

Schwannosis: role of gliosis and proteoglycan in human spinal cord injury

Schwannosis (aberrant proliferation of Schwann cells and nerve fibers) has been reported following spinal cord injury (SCI). In this study, we examined the incidence of schwannosis following human SCI, and investigated its relationship to gliosis. We found evidence of schwannosis in 32 out of 65 cases (48%) of human SCI that survived 24 h to 24 years after injury; this incidence rose to 82% in those patients who survived for more than 4 months. Schwannosis was not observed in cases that survived less than 4 months after injury. In affected cases, it was generally noted in areas that had low immunoreactivity for glial fibrillary acidic protein (GFAP), suggesting that reduced gliosis might have contributed to the aberrant proliferation of Schwann cells following SCI. Since chondroitin sulfate proteoglycan (CSPG) has been proposed to play a role in Schwann cell/glial interaction, we performed immunohistochemical staining for CSPG to investigate its potential relationship with schwannosis. CSPG in the injured cord was generally associated with the blood vessel walls, but was also sometimes noted in reactive astrocytes. In SCI with schwannosis, CSPG staining was more prominent and confined largely to the extracellular matrix and basal lamina of proliferating Schwann cells. Our study suggests that Schwann cells, which may have been displaced from spinal roots and introduced into the injured cord through a break in the pial surface, are capable of proliferating and producing CSPG, particularly in the setting of reduced gliosis. Since CSPG has been associated with inhibition of neurite outgrowth, its increased production by aberrant Schwann cells may impair spinal cord regeneration after injury.     

Open MRI-Guided Microsurgery of Intracranial Tumours. Preliminary Experience Using a Vertical Open MRI-Scanner

Summary ? Objectives. A number of different image-guided surgical techniques have been developed during the past decade. None of these methods can provide the surgeon with information about the dynamic changes that occur intra-operatively. The development of open configurated MRI-scanners leads to new perspectives in the intra-operative management and resection control of intracranial tumours.  Material and Method. Using a vertical open 0.5 T MRI-scanner for intra-operative MR image guided neurosurgery, forty-four patients (20 female/24 male) with different intracranial tumours have been operated on since August 1997. The patients ranged in age from 20 to 70 years (mean±standard deviation=47.2±15.9 ys).  Results. In 36 (82%) of 44 patients the tumours were completely removed with the aid of MR image-guidance. In 8 cases (18%) complete removal was not achieved. Postoperatively 6 (14%) of 44 patients developed neurological deficits which were transient in 5 cases (paresis, dysphasia). In these patients the tumours were located in or near eloquent brain areas (sensorimotor cortex/speech center).  Conclusion. Intra-operative MRI is helpful for navigation as well as determining of tumour margins to achieve a complete and safe resection of intracranial lesions. Complications related to the surgical procedure are reduced and the risk of neurological deterioration due to tumour removal and postoperative complications is minimized. It can be concluded that the intra-operative application of interventional MRI technology may represent a major step foreward in the field of neurosurgery.     

Australia's notifiable diseases status, 2002: Annual report of the National Notifiable Diseases Surveillance System.

There were 57 infectious diseases notifiable at the national level in Australia in 2002. States and territories reported 100,278 cases of infectious diseases to the National Notifiable Diseases Surveillance System (NNDSS), a fall of 4 per cent compared to the number of notifications in 2001. In 2002, the most frequently notified diseases were, sexually transmitted infections (31,929 reports, 32% of total notifications), gastrointestinal infections (26,708 reports, 27% of total notifications) and bloodborne infections (23,741, 24%). There were 11,711 (12% of total) cases of vaccine preventable diseases, 3,052 (3% of total) cases of vectorborne diseases, 1,155 (1% of total) cases of zoonotic infections, two cases of quarantinable diseases (Vibrio cholerae O1) and 1,980 cases of other bacterial diseases, notified to NNDSS. Compared to 2001, notifications of sexually transmitted infections increased by 16 per cent and gastrointestinal infections by 2 per cent while bloodborne infections fell by 18 per cent. The number of notifications of chlamydial infection and Q fever were the highest since 1991 and 1995 respectively. By contrast, the number of notification for hepatitis A and measles were the lowest since 1991. For other notifiable diseases, the number of notifications was within the range of the five years between 1997 and 2002 (range = five-year mean plus or minus two standard deviations). This report also includes 2002 summary data on communicable diseases from other surveillance systems including the Laboratory Virology and Serology Reporting Scheme and sentinel general practitioner schemes.     

Emotion/cognition-coupling in word recognition memory of depressive patients: an event-related potential study

Depressive patients show deficits in memory functions. However, the underlying mechanisms remain unclear. Experiments with a special emphasis on the link between emotion and cognition appear challenging. The aim of this study is to investigate the influence of the emotional content of words on memory in non-medicated depressive patients (n=11) compared with a control group (n=11) utilizing event-related brain potentials (ERPs). In a continuous word recognition paradigm brain responses to repeated items are characterized by more positive waveforms of ERPs. This recognition effect ('old/new effect') has been shown to be sensitive to parameters relevant for memory processing. For the purpose of this ERP experiment visually presented words were classified into three different categories of emotional content. The ERPs for the correctly detected 'old' (repeated) words showed an increased positivity beginning approximately 250 ms post-stimulus, concurring with a good recognition performance. In addition, old/new effect and behavioral data were sensitive to words' different emotional connotations in the control group. In contrast, the depressive patients performed worse and showed no significant old/new effect. Nevertheless, their recognition performance was also enhanced by the emotional content. Furthermore, a differential effect of the emotional content on frontal ERPs was found between groups. In contrast to the control group, a reduced old/new effect indicates a reduced working memory capacity in the moderately depressed patients. This is suggested to be partially due to changes of the emotion/cognition coupling related to ruminations with preferably negative emotional connotation. However, the emotional content also affects recognition performance in the depressive patients.     

Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.     

A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity.

BACKGROUND: To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks. RESULTS: Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (<5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P < 0.01), mood (P < 0.05), functional performance (P < 0.05) and less effort to cope (P < 0.05) compared with the non-responders and stable disease patients. CONCLUSIONS: The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.     

Occurrence and elimination of cyanobacterial toxins in two Australian drinking water treatment plants.

In Australian freshwaters, Anabaena circinalis, Microcystis spp. and Cylindrospermopsis raciborskii are the dominant toxic cyanobacteria. Many of these surface waters are used as drinking water resources. Therefore, the National Health and Medical Research Council of Australia set a guideline for MC-LR toxicity equivalents of 1.3 microg/l drinking water. However, due to lack of adequate data, no guideline values for paralytic shellfish poisons (PSPs) (e.g. saxitoxins) or cylindrospermopsin (CYN) have been set. In this spot check, the concentration of microcystins (MCs), PSPs and CYN were determined by ADDA-ELISA, cPPA, HPLC-DAD and/or HPLC-MS/MS, respectively, in two water treatment plants in Queensland/Australia and compared to phytoplankton data collected by Queensland Health, Brisbane. Depending on the predominant cyanobacterial species in a bloom, concentrations of up to 8.0, 17.0 and 1.3 microg/l were found for MCs, PSPs and CYN, respectively. However, only traces (<1.0 microg/l) of these toxins were detected in final water (final product of the drinking water treatment plant) and tap water (household sample). Despite the low concentrations of toxins detected in drinking water, a further reduction of cyanobacterial toxins is recommended to guarantee public safety.     

Glycogen synthase sensitivity to insulin and glucose-6-phosphate is mediated by both NH2- and COOH-terminal phosphorylation sites

In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase. To study the mechanism of regulation of glycogen synthase by insulin and glucose-6-phosphate, we generated stable Rat-1 fibroblast clones expressing rabbit muscle glycogen synthase with Ser-->Ala substitutions at key phosphorylation sites. We found that 1) elimination of the phosphorylation of either NH2- or COOH-terminal sites did not abolish insulin stimulation of glycogen synthase; 2) mutations at both Ser-7 and Ser-640 were necessary to bypass insulin activation; 3) mutation at Ser-7, coupled with the disruption of the motif for recognition by glycogen synthase kinase-3 (GSK-3), did not eliminate the insulin effect; and 4) mutation of either Ser-7 or Ser-640 increased the sensitivity of glycogen synthase to glucose 6-phosphate >10-fold. We conclude that Ser-7 and Ser-640 are both involved in mediating the response of glycogen synthase to insulin and activation by glucose 6-phosphate. In Rat-1 fibroblasts, GSK-3 action is not essential for glycogen synthase activation by insulin, and GSK-3-independent mechanisms also operate.