Intrathecal neurotensin is hypotensive, sympathoinhibitory and enhances the baroreflex in anaesthetized rat

BACKGROUND AND PURPOSE The neuromodulatory effects of the gut-neuropeptide neurotensin on sympathetic vasomotor tone, central respiratory drive and adaptive reflexes in the spinal cord, are not known. EXPERIMENTAL APPROACH Neurotensin (0.5 µM-3 mM) was administered into the intrathecal (i.t.) space at the sixth thoracic spinal cord segment in urethane-anaesthetized, paralysed, vagotomized male Sprague-Dawley rats. Pulsatile arterial pressure, splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, ECG and end-tidal CO(2) were recorded. KEY RESULTS Neurotensin caused a dose-related hypotension, sympathoinhibition and bradycardia. The maximum effects were observed at 3000 µM, where the decreases in mean arterial pressure (MAP), heart rate (HR) and sSNA reached -25 mmHg, -26 beats min(-1) and -26% from baseline, respectively. The sympathetic baroreflex was enhanced. Changes in central respiratory drive were characterized by a fall in the amplitude of the phrenic nerve activity. Finally, administration of SR 142948A (5 mM), a potent, selective antagonist at neurotensin receptors, caused a potent hypotension (-35 mmHg), bradycardia (-54 beats min(-1) ) and sympathoinhibition (-44%). A reduction in the amplitude and frequency of the phrenic nerve activity was also observed. CONCLUSIONS AND IMPLICATIONS The data demonstrate that neurotensin plays an important role in the regulation of spinal cardiovascular function, affecting both tone and adaptive reflexes.12 page(s

Intrathecal bombesin is sympathoexcitatory and pressor in rat

Bombesin, a 14 aminoacid peptide, is pressor when administered intravenously in rat and pressor and sympathoexcitatory when applied intracerebroventricularly. To determine the spinal effects of bombesin, the peptide was administered acutely in the intrathecal space at around thoracic spinal cord level six of urethane-anesthetized, paralyzed, and bilaterally vagotomized rats. Blood pressure, heart rate, splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, and end-tidal CO2 were monitored to evaluate changes in the cardiorespiratory systems. Bombesin elicited a long-lasting excitation of sSNA associated with an increase in blood pressure and tachycardia. There was a mean increase in arterial blood pressure of 52 ± 5 mmHg (300 μM; P < 0.01). Heart rate and sSNA also increased by 40 ± 4 beats/min (P < 0.01) and 162 ± 33% (P < 0.01), respectively. Phrenic nerve amplitude (PNamp, 73 ± 8%, P < 0.01) and phrenic expiratory period (+0.16 ± 0.02 s, P < 0.05) increased following 300 μ M bombesin. The gain of the sympathetic baroreflex increased from -2.8 ± 0.7 to -5.4 ± 0.9% (P < 0.01), whereas the sSNA range was increased by 99 ± 26% (P < 0.01). During hyperoxic hypercapnia (10% CO2 in O2, 90 s), bombesin potentiated the responses in heart rate (-25 ± 5 beats/min, P < 0.01) and sSNA (+136 ± 29%, P < 0.001) but reduced PNamp (from 58 ± 6 to 39 ± 7%, P < 0.05). Finally, ICI-216,140 (1 mM), an in vivo antagonist for the bombesin receptor 2, attenuated the effects of 300 μM bombesin on blood pressure (21 ± 7 mmHg, P < 0.01). We conclude that bombesin is sympathoexcitatory at thoracic spinal segments. The effect on phrenic nerve activity may the result of spinobulbar pathways and activation of local motoneuronal pools.8 page(s

Development of an intensive mode neuroanatomy unit utilising the Flipped Classroom

In 2011, Macquarie University opted for an intensive mode session three during the summer break, which compressed a traditional teaching program of 13 weeks into a shorter block session of five weeks. In that year, the Department of Chiropractic ran an intensive mode neuroanatomy unit. To do this, the traditional offering for that course was offered in the compressed timeframe without change to curriculum, learning outcomes, teachers or format of the course. The pre-recorded lectures were made available online, and the practical and tutorial content and time was retained. The outcomes that were collected and compared with those attained that year in the traditional offering were the standard numerical grades (SNGs) and the results of a questionnaire that measured student satisfaction with the course. The cohort in session three did significantly worse (p = 0.001). However, the overall satisfaction with the course was the same for the two cohorts. This experience demonstrated the necessity for considerable change in teaching strategy when transitioning a unit taught traditionally to intensive mode delivery. Without such change, the quality of the learner experience may be severely impacted. We have looked to the Flipped Classroom teaching model to redevelop this unit for the upcoming session three, 2013, and will compare the same outcome measures of this cohort to the first session three and to the traditional mode session two cohort of 2013, with the aim of measuring whether this is an effective way to improve learning and teaching in an intensive mode delivery of the course.6 page(s

Current trends in clinical genetics of colorectal cancer

Recent innovations in molecular biology and colorectal cancer (CRC) genetics have facilitated the understanding of the pathogenesis of sporadic and hereditary CRC syndromes. The development of technology has enabled data collection for a number of genetic factors, which lead to understanding of the molecular mechanisms underlying CRC. The incidence and the nature of CRC is a mixture of genetic and environmental factors. The current field of interest is to understand how molecular basis could shape predisposition for developing CRC, disease progression and response to chemotherapy. In this article, we summarize new and developing genetic markers, and assess their clinical value for inherited and sporadic CRC

Intermittent activation of peripheral renin-angiotensin system (RAS) elicits sympathetic long term facilitation (LTF)

We recently reported that acute intermittent hypoxia (AIH, 10x45s of 10% O₂, 5 min intervals) produces LTF of splanchnic sympathetic nerve activity (sSNA), independent of respiratory LTF (Xing & Pilowsky, 2010, J Physiol, 588:3075). We hypothesised that sympathetic LTF (sLTF) is the result of intermittent activation of RAS, by renal hypoxia caused by AIH-evoked hypotension. We recorded phrenic nerve activity (PNA) and sSNA, in anesthetised (pentobarbitone, 60mg/kg, ip), vagotomised, and ventilated Sprague-Dawley rats. Intermittent bolus injections of angiotensin II (Ang, 10x35pmol in 0.1ml, iv), at the same 5 min intervals as AIH, elicited sLTF (+42.4 ±11.5%, n=5). Intermittent phenylephrine (PE, 10x 25μg in 0.1mL, iv) also produced sLTF (+72.4±21.6%, n=5), possibly via renal vasoconstriction induced renin release. Intermittent sodium nitroprusside induced hypotension (10x50μg in 0.1mL, iv) did not elicit sLTF (+2.4±5.6%, n=5). Infusion of Ang (350pmol in 1mL) or PE (250μg in 1mL) over 10 mins, also did not cause sLTF, indicating that intermittent stimulation of RAS is essential for sLTF to develop. PNA was unchanged in all groups. This data supports the idea that sLTF and respiratory LTF are mediated by separate mechanisms and that intermittent stimulation of peripheral RAS may be sufficient to elicit sLTF. This data may be relevant to sympathetic overactivity in sleep apnea patients. Funded by NH&MRC, ARC.1 page(s

Microsatellite instability & survival in patients with stage II/III colorectal carcinoma

Background & objectives: The two key aspects associated with the microsatellite instability (MSI) as genetic phenomenon in colorectal cancer (CRC) are better survival prognosis, and the varying response to 5-fluorouracil (5-FU)-based chemotherapy. This study was undertaken to measure the survival of surgically treated patients with stages II and III CRC based on the MSI status, the postoperative 5-FU treatment as well as clinical and histological data. Methods: A total of 125 consecutive patients with stages II and III (American Joint Committee on Cancer, AJCC staging) primary CRCs, were followed prospectively for a median time of 31 months (January 2006 to December 2009). All patients were assessed, operated and clinically followed. Tumour samples were obtained for cytopathological verification and MSI grading. Results: Of the 125 patients, 21 (20%) had high MSI (MSI-H), and 101 patients (80%) had MSI-L or MSS (low frequency MSI or stable MSI). Patients with MSS CRC were more likely to have recurrent disease (P=0.03; OR=3.2; CI 95% 1-10.2) compared to those with MSI-H CRC. Multi- and univariate Cox regression analysis failed to show a difference between MSI-H and MSS groups with respect to disease-free, disease-specific and overall survival. However, the disease-free survival was significantly lower in patients with MSI-H CRC treated by adjuvant 5-FU therapy (P=0.03). Interpretation & conclusions: MSI-H CRCs had a lower recurrence rate, but the prognosis was worse following adjuvant 5-FU therapy

Effective notification of important non-urgent radiology results : a qualitative study of challenges and potential solutions

Introduction: We report on the implementation of a Radiology Notification System (RNS), set up by the medical imaging department of a major Sydney teaching hospital in March 2010. This study aimed to investigate the views of the medical imaging department staff about: (i) the results follow-up problem encountered by the medical imaging department prior to the implementation of the RNS; (ii) what changes occurred following implementation of the RNS; and (iii) suggestions for improving the RNS. Methods: This is a cross-sectional qualitative study incorporating semi-structured interviews with 16 staff (15 radiologists and 1 clerk) after the implementation of the RNS. Interviews were conducted in August/September 2011. Results: The reasons behind the development of the RNS were related to: (i) major existing problems with the communication of results between the imaging department and hospital wards; (ii) cumbersome and inefficient paper-based notification systems; and (iii) the absence of standardised guidelines and procedures for radiology test notification and follow-up. The RNS managed to free up a significant proportion of radiologist time, resulting in greater efficiencies. Study participants also highlighted a number of areas for improvement, including the need for a 24-h service, feedback and acknowledgement of test results by clinicians and the standardisation of test management definitions and procedures. Conclusion: Test management systems can play an important part in enhancing safe and effective communications between wards and hospital departments. However, their uptake and sustainability will require the establishment of a multidisciplinary and hospital-wide collaboration that includes clinicians

Microsatellite instability & survival in patients with stage II/III colorectal carcinoma

Background & objectives: The two key aspects associated with the microsatellite instability (MSI) as genetic phenomenon in colorectal cancer (CRC) are better survival prognosis, and the varying response to 5-fluorouracil (5-FU)-based chemotherapy. This study was undertaken to measure the survival of surgically treated patients with stages II and III CRC based on the MSI status, the postoperative 5-FU treatment as well as clinical and histological data. Methods: A total of 125 consecutive patients with stages II and III (American Joint Committee on Cancer, AJCC staging) primary CRCs, were followed prospectively for a median time of 31 months (January 2006 to December 2009). All patients were assessed, operated and clinically followed. Tumour samples were obtained for cytopathological verification and MSI grading. Results: Of the 125 patients, 21 (20%) had high MSI (MSI-H), and 101 patients (80%) had MSI-L or MSS (low frequency MSI or stable MSI). Patients with MSS CRC were more likely to have recurrent disease (P=0.03; OR=3.2; CI 95% 1-10.2) compared to those with MSI-H CRC. Multi- and univariate Cox regression analysis failed to show a difference between MSI-H and MSS groups with respect to disease-free, disease-specific and overall survival. However, the disease-free survival was significantly lower in patients with MSI-H CRC treated by adjuvant 5-FU therapy (P=0.03). Interpretation & conclusions: MSI-H CRCs had a lower recurrence rate, but the prognosis was worse following adjuvant 5-FU therapy

Microsatellite instability affecting the T17 repeats in intron 8 of HSP110, as well as five mononucleotide repeats in patients with colorectal carcinoma

Aim: To investigate mononucleotide markers: BAT-25, BAT-26, NR-21, NR-22 and NR-24 in patients with colorectal cancer (CRC), and the status of HSP110T17, KRAS, BRAF and the MLH1 promoter mutations in microsatellite unstable CRC. Methods: Genetic assessments were performed on samples obtained following resection of CRC in 200 patients. Results: Allelic variations of HSP110T17 were found in all 18 patients with microsatellite instabilities (MSIs) in at least three markers (high-frequency MSI). By contrast, mutations of HSP110T17 were absent in all 20 patients with no MSI frequency. Eight out of 182 patients with low (instability in one marker) or no frequency MSI had allelic shifts due to polymorphisms of BAT-25 (1.5%), NR-21 (1.75%) and NR-24 (1.5%). BRAF mutations were associated with >5 bp shortening of HSP110T17. Conclusion: Patients with high-frequency MSI CRC had allelic variations of HSP110T17. BRAF mutations occur along with greater shortening in HSP110T17 during oncogenesis via the MSI pathway

A comparison between radiation therapists and medical specialists in the use of kilovoltage cone-beam computed tomography scans for potential lung cancer radiotherapy target verification and adaptation

Target volume matching using cone-beam computed tomography (CBCT) is the preferred treatment verification method for lung cancer in many centers. However, radiation therapists (RTs) are trained in bony matching and not soft tissue matching. The purpose of this study was to determine whether RTs were equivalent to radiation oncologists (ROs) and radiologists (RDs) in alignment of the treatment CBCT with the gross tumor volume (GTV) defined at planning and in delineating the GTV on the treatment CBCT, as may be necessary for adaptive radiotherapy. In this study, 10 RTs, 1 RO, and 1 RD performed a manual tumor alignment and correction of the planning GTV to a treatment CBCT to generate an isocenter correction distance for 15 patient data sets. Participants also contoured the GTV on the same data sets. The isocenter correction distance and the contoured GTVs from the RTs were compared with the RD and RO. The mean difference in isocenter correction distances was 0.40. cm between the RO and RD, 0.51. cm between the RTs, and RO and 0.42. cm between the RTs and RD. The 95% CIs were smaller than the equivalence limit of 0.5. cm, indicating that the RTs were equivalent to the RO and RD. For GTV delineation comparisons, the RTs were not found to be equivalent to the RD or RO. The alignment of the planning defined GTV and treatment CBCT using soft tissue matching by the RTs has been shown to be equivalent to those by the RO and RD. However, tumor delineation by the RTs on the treatment CBCT was not equivalent to that of the RO and RD. Thus, it may be appropriate for RTs to undertake soft tissue alignment based on CBCT; however, further investigation may be necessary before RTs undertake delineation for adaptive radiotherapy purposes