Real-world adjuvant chemotherapy treatment patterns and outcomes over time for resected stage II and III colorectal cancer.

BACKGROUND: The administration of adjuvant chemotherapy (AC) to colorectal cancer (CRC) patients in Australia and impact of recent trial data has not been well reported. We aim to evaluate temporal trends in AC treatment and outcomes in real-world Australian patients. METHODS: CRC patients were analyzed from 13 hospitals, stratified by stage (II or III) and three 5-year time periods (A: 2005-2009, B: 2010-2014, C: 2015-2019). Stage III was further stratified as pre- and post publication of the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration (March 2018). AC prescription, time-to-recurrence (TTR), and overall survival (OS) was compared across the time periods. RESULTS: Of 3977 identified patients, 1148 (stage II: 640, stage III: 508), 1525 (856 vs. 669), and 1304 (669 vs. 635) were diagnosed in Period A, B, and C, respectively. Fewer patients in Period C received AC compared to Period B in stage II (10% vs. 15%, p <.01) and III (70% vs. 79%, p <.01). Post-IDEA, the proportion of patients receiving ≤3 months of oxaliplatin-based AC increased (45% vs. 13%, p <.01). The proportion of patients who remained recurrence free at 3 years was similar between time periods in stage II (A: 89% vs. B: 88% vs. C: 90%, p = .53) and stage III (72% vs. 76% vs. 72%, p = .08). OS significantly improved for stage II (80%-85%, p = .04) and stage III (69%-77%, <.01) from period A to B. CONCLUSION: AC use has moderately decreased over time with no impact on recurrence rates. Improved survival in more recent years despite similar recurrence rates may be related to improved baseline staging, better postrecurrence treatment, and reduced noncancer-related mortality.

A randomized, controlled study to assess if allopathic-osteopathic collaboration influences stereotypes, interprofessional readiness, and doctor-patient communication.

Despite the growing similarities between allopathic (MD) and osteopathic (DO) medical education, few studies have examined allopathic-osteopathic collaboration. The following study focused on stereotypes and student readiness for interprofessional learning. Patient perceptions were also evaluated. Osteopathic and allopathic students were randomly allocated 1:1:1 to work in pairs (MD/DO, MD/MD, DO/DO) at the start of each shift. A questionnaire evaluating student communication was collected from patients at the end of each encounter. Surveys assessing stereotypes and interprofessional readiness were obtained from students at the end of each workday. Data collection was stopped early due to Coronavirus-related safety measures. In the ITT analysis, there were a total of 126 participants (57 students 69 patients). A per-protocol analysis was performed to account for repeat clinic volunteers. No significant differences were detected between student pairs; however, the sensitivity analysis of the questionnaire assessing interprofessional readiness was 8 points higher in the DO/DO group compared to the MD/MD and MD/DO groups (P = 0.0503). In the content analysis of qualitative responses, the MD/DO group was more likely to respond with themes of enjoyment and less concern about stereotypes than the DO/DO group. The MD/DO group was also less likely to report concerns about differences in expectations, methods, and thinking than the MD/MD group. Early trends from this study suggest that DO students may be better positioned to engage in interprofessional learning than their MD counterparts. Additionally, the findings from our content analysis provide evidence that the collaborative experience improved feelings associated with professional legitimacy and credibility among DO students. Taken in aggregate, this study provides justification for a follow-up investigation, as well as a framework for how such studies could best be executed in the future.

The impact of a mindfulness bracelet on emotional affect in medical students: a prospective cohort study.

BACKGROUND: There is concern that negative changes in emotional outlook among medical students may impair the behavior of students, diminish learning, and ultimately affect patient care. Although most medical students begin their professional education with idealism, enthusiasm, and attention to humanity, they often have difficulty balancing their happiness with social and professional responsibilities. The following study aimed to determine if a simple mindfulness reminder (in the form of a bracelet) will impact emotional affect in first-year medical students. The second aim is to better understand the changes in emotional affect as students start medical school. METHODS: First year medical students were invited to participate at the start of the academic year. Baseline survey data and demographic data were obtained prior to participants being given the mindfulness bracelet and a standardized presentation explaining its purpose. Follow-up surveys were obtained at one- and two-month intervals. Statistical analysis was based on sum score of the survey. Change of sum score over time was tested by using repeated measurement analysis. RESULTS: Data collection included 104 students at the initial distribution of the survey. Follow-up surveys were obtained from 78 and 69 students at the first- and second-month mark, respectively. No significant associations were detected between frequency of mindfulness bracelet usage and emotional affect. However, there was a significant decrease in positive affect over the first month of medical school (p < 0.01), followed by a significant recovery in positive affect in the second month of medical school (p < 0.01). Demographic data did not reveal statistically significant differences among demographic groups and progression of emotional affect. CONCLUSIONS: Although the mindfulness bracelet intervention did not yield significant improvement in emotional affect, our results are consistent with other studies demonstrating that the first year of medical school negatively impacts the emotional outlook of students. Future studies are needed to explore practical interventions and to better understand and address the negative effect that early medical school education has on student's emotional state.

Annual water residence time effects on thermal structure: A potential lake restoration measure?

Innovative methods to combat internal loading issues in eutrophic lakes are urgently needed to speed recovery and restore systems within legislative deadlines. In stratifying lakes, internal phosphorus loading is particularly problematic during the summer stratified period when anoxia persists in the hypolimnion, promoting phosphorus release from the sediment. A novel method to inhibit stratification by reducing residence times is proposed as a way of controlling the length of the hypolimnetic anoxic period, thus reducing the loading of nutrients from the sediments into the water column. However, residence time effects on stratification length in natural lakes are not well understood. We used a systematic modelling approach to investigate the viability of changes to annual water residence time in affecting lake stratification and thermal dynamics in Elterwater, a small stratifying eutrophic lake in the northwest of England. We found that reducing annual water residence times shortened and weakened summer stratification. Based on finer-scale dynamics of lake heat fluxes and water column stability we propose seasonal or sub-seasonal management of water residence time is needed for the method to be most effective at reducing stratification as a means of controlling internal nutrient loading.

Can reductions in water residence time be used to disrupt seasonal stratification and control internal loading in a eutrophic monomictic lake?

Anthropogenic eutrophication caused by excess loading of nutrients, especially phosphorus (P), from catchments is a major cause of lake water quality degradation. The release of P from bed sediments to the water column, termed internal loading, can exceed catchment P load in eutrophic lakes, especially those that stratify during warm summer periods. Managing internal P loading is challenging, and although a range of approaches have been implemented, long-term success is often limited, requiring lake-specific solutions. Here, we assess the manipulation of lake residence time to inhibit internal loading in Elterwater, a shallow stratifying lake in the English Lake District, UK. Since 2016, additional inflowing water has been diverted into the inner basin of Elterwater to reduce its water residence time, with the intention of limiting the length of the stratified period and reducing internal loading. Combining eight years of field data in a Before-After-Control-Impact study with process-based hydrodynamic modelling enabled the quantification of the residence time intervention effects on stratification length, water column stability, and concentrations of chlorophyll a and P. Annual water residence time was reduced during the study period by around 40% (4.9 days). Despite this change, the lake continued to stratify and developed hypolimnetic anoxia. As a result, there was little significant change in phosphorus (as total or soluble reactive phosphorus) or chlorophyll a concentrations. Summer stratification length was 2 days shorter and 7% less stable with the intervention. Our results suggest that the change to water residence time in Elterwater was insufficient to induce large enough physical changes to improve water quality. However, the minor physical changes suggest the management measure had some impact and that larger changes in water residence time may have the potential to induce reductions in internal loading. Future assessments of management requirements should combine multi-year observations and physical lake modelling to provide improved understanding of the intervention effect size required to alter the physical structure of the lake, leading to increased hypolimnetic oxygen and reduced potential for internal loading.

Early management of meconium ileus in infants with cystic fibrosis: A prospective population cohort study.

BACKGROUND: Contemporary early outcome data of meconium Ileus (MI) in cystic fibrosis (CF) are lacking on a population level. We describe these and explore factors associated with successful non-operative management. METHODS: A prospective population-cohort study using an established surveillance system (BAPS-CASS) was conducted October 2012-September 2014. Live-born infants with bowel-obstruction from inspissated meconium in the terminal ileum and CF were reported. Data are described as median (interquartile range, IQR). RESULTS: 56 infants were identified. 14/56(25%) had primary laparotomy (13/23 complicated MI, 1/33 simple), the remainder underwent contrast enema. Twelve, (12/33 (36%) with simple MI) achieved decompression. 8/12 (67%) who decompressed had >1 enema vs 3/20 (15%) with simple MI who had laparotomy after enema. The number of enemas per infant (1-4), contrast agents and their concentration, were highly variable. Enterostomy was formed at 24/44(55%) of laparotomies. In infants with simple MI, time to full enteral feeds was 6 (2-10) days in those decompressing with enema vs 15 (9-19) days with laparotomy after enema. Case fatality was 4% (95% CI 0.4-12%). Two infants, both preterm died, both in the second month after birth. CONCLUSIONS: Infants with simple MI achieving successful enema decompression were more likely to have had repeat enemas than those who proceeded to laparotomy. Successful non-operative management was associated with a shorter time to full feeds. The early management of infants with MI is highly variable and not standardised across the UK and Ireland.

Sound detection by the American lobster (Homarus americanus).

Although many crustaceans produce sounds, their hearing abilities and mechanisms are poorly understood, leaving uncertainties regarding whether or how these animals use sound for acoustic communication. Marine invertebrates lack gas-filled organs required for sound pressure detection, but some of them are known to be sensitive to particle motion. Here, we examined whether the American lobster (Homarus americanus) could detect sound and subsequently sought to discern the auditory mechanisms. Acoustic stimuli responses were measured using auditory evoked potential (AEP) methods. Neurophysiological responses were obtained from the brain using tone pips between 80 and 250 Hz, with best sensitivity at 80-120 Hz. There were no significant differences between the auditory thresholds of males and females. Repeated controls (recordings from deceased lobsters, moving electrodes away from the brain and reducing seawater temperature) indicated the evoked potentials' neuronal origin. In addition, AEP responses were similar before and after antennules (including statocysts) were ablated, demonstrating that the statocysts, a long-proposed auditory structure in crustaceans, are not the sensory organs responsible for lobster sound detection. However, AEPs could be eliminated (or highly reduced) after immobilizing hairfans, which cover much of lobster bodies. These results suggest that these external cuticular hairs are likely to be responsible for sound detection, and imply that hearing is mechanistically possible in a wider array of invertebrates than previously considered. Because the lobsters' hearing range encompasses the fundamental frequency of their buzzing sounds, it is likely that they use sound for intraspecific communication, broadening our understanding of the sensory ecology of this commercially vital species. The lobsters' low-frequency acoustic sensitivity also underscores clear concerns about the potential impacts of anthropogenic noise.

Improved outcomes utilizing a novel pectin-based pleural sealant following acute lung injury.

BACKGROUND: Persistent air leaks after thoracic trauma are associated with significant morbidity. To evaluate a novel pectin sealant in a swine model of traumatic air leaks, we compared a pectin biopolymer with standard surgical and fibrin-based interventions. METHODS: A standardized lung injury was created in male Yorkshire swine. Interventions were randomized to stapled wedge resection (n = 5), topical fibrin glue (n = 5), fibrin patch (n = 5), and a pectin sealant (n = 6). Baseline, preintervention and postintervention tidal volumes (TV) were recorded. Early success was defined as the return to near-normal TV (>95% of baseline). Late success was defined as no detectable air leak in the chest tube after chest closure. RESULTS: There were no differences in injury severity between groups (mean TV loss, 62 ± 17 mL, p = 0.2). Early success was appreciated in 100% (n = 6) of the pectin interventions which was significantly better than the fibrin sealant (20%, n = 1), fibrin patch (20%, n = 1), and stapled groups (80%, n = 4, p = 0.01). The percent of return to baseline TV after sealant intervention was significantly increased in the pectin (98%) and staple arms (97%) compared with the fibrin sealant (91%) and fibrin patch arms (90%) (p = 0.02; p = 0.03). Late success was also improved with the pectin sealant: no air leak was detected in 83% of the pectin group compared with 40% in the stapled group (p = 0.008)-90% of the fibrin-based interventions resulted in continuous air leaks (p = 0.001). CONCLUSION: Pectin-based bioadhesives effectively seal traumatic air leaks upon application in a porcine model. Further testing is warranted as they may provide a superior parenchymal-sparing treatment option for traumatic air leaks.

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes.

OBJECTIVE: Tumour-infiltrating lymphocyte (TIL) response and deficient DNA mismatch repair (dMMR) are determinants of prognosis in colorectal cancer. Although highly correlated, evidence suggests that these are independent predictors of outcome. However, the prognostic significance of combined TIL/MMR classification and how this compares to the major genomic and transcriptomic subtypes remain unclear. DESIGN: A prospective cohort of 1265 patients with stage II/III cancer was examined for TIL/MMR status and BRAF/KRAS mutations. Consensus molecular subtype (CMS) status was determined for 142 cases. Associations with 5-year disease-free survival (DFS) were evaluated and validated in an independent cohort of 602 patients. RESULTS: Tumours were categorised into four subtypes based on TIL and MMR status: TIL-low/proficient-MMR (pMMR) (61.3% of cases), TIL-high/pMMR (14.8%), TIL-low/dMMR (8.6%) and TIL-high/dMMR (15.2%). Compared with TIL-high/dMMR tumours with the most favourable prognosis, both TIL-low/dMMR (HR=3.53; 95% CI=1.88 to 6.64; Pmultivariate<0.001) and TIL-low/pMMR tumours (HR=2.67; 95% CI=1.47 to 4.84; Pmultivariate=0.001) showed poor DFS. Outcomes of patients with TIL-low/dMMR and TIL-low/pMMR tumours were similar. TIL-high/pMMR tumours showed intermediate survival rates. These findings were validated in an independent cohort. TIL/MMR status was a more significant predictor of prognosis than National Comprehensive Cancer Network high-risk features and was a superior predictor of prognosis compared with genomic (dMMR, pMMR/BRAFwt /KRASwt , pMMR/BRAFmut /KRASwt , pMMR/BRAFwt /KRASmut ) and transcriptomic (CMS 1-4) subtypes. CONCLUSION: TIL/MMR classification identified subtypes of stage II/III colorectal cancer associated with different outcomes. Although dMMR status is generally considered a marker of good prognosis, we found this to be dependent on the presence of TILs. Prognostication based on TIL/MMR subtypes was superior compared with histopathological, genomic and transcriptomic subtypes.

Embedded Game Design as a Method for Addressing Social Determinants of Health.

This paper, describes the design, development, and evaluation of The Test, a theory-based mobile game prototype designed to promote HIV testing by providing information and influencing motivations, and behavioral intentions among YMSM. The Test was designed using embedded design, first described by Kaufman & Flanagan (2015), which diverges from traditional "educational game" design strategies by mixing on-message content with nonfocal content, in an attempt to make the overall experience more approachable and engaging. One challenge of embedded design is that it targets attitudes and actions that are not always proximate to a particular behavior. Games with embedded content forgo explicit takeaways, and their possible distal effects present a challenge to traditional tests of efficacy. The benefit of embedded design, however, is that its holistic or ecological design approach (which considers feelings, emotions, affects, social relations, and connections to broader communities) stands in close alignment with the social-ecological model.

Impact of Surgical Complications Following Resection of Locally Advanced Rectal Adenocarcinoma on Adjuvant Chemotherapy Delivery and Survival Outcomes.

BACKGROUND: Surgical complications after resection for locally advanced rectal cancer may influence adjuvant treatment outcomes and survival. Few studies have examined this effect. OBJECTIVE: This study aimed to examine the impact of surgical complications on adjuvant therapy delivery and survival in patients with locally advanced rectal cancer treated with long-course chemoradiation followed by surgery. DESIGN: This is a retrospective analysis of a prospectively collected multicenter colorectal cancer database. SETTINGS: Data were collected from the Australian Comprehensive Cancer Outcomes and Research Database. PATIENTS: All patients who completed neoadjuvant chemoradiotherapy followed by surgery for locally advanced rectal cancer between January 2003 and December 2014 were selected. MAIN OUTCOME MEASURES: We examined the types and frequency of surgical complications and their impact on the delivery of adjuvant chemotherapy and survival. RESULTS: Data were available for 517 patients, of whom 147 (28%) had a surgical complication. Patients with a surgical complication were less likely to commence adjuvant chemotherapy (33% vs 66%; p = 0.0005) and more likely to have adjuvant treatment commencing more than 8 weeks from surgery (71.8% vs 21.2%; p = 0.004). Wound-related complications (p = 0.001), return to operating theater (p = 0.004), and readmission within 30 days (p = 0.02) had the most significant negative impact on the delivery of adjuvant chemotherapy. Surgical complications were significantly more likely in males (31.6% vs 20.8%, p = 0.003) and laparoscopic converted cases (47.8% vs 21.8%, p = 0.03). For the entire patient population, adjuvant chemotherapy compared with surveillance was not associated with an improved recurrence-free survival (HR, 1.06; p = 0.83) but was associated with an improved overall survival (HR, 0.53; p = 0.04). LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Surgical complications in patients having surgery following neoadjuvant chemoradiotherapy for locally advanced rectal cancer were associated with significantly reduced uptake and delays to receiving adjuvant therapy. Surgical complications, however, were not associated with either significantly reduced recurrence-free or overall survival. Adjuvant chemotherapy delivery was associated with improved overall survival.

Implementation of a standardized pathway for the treatment of cardiac arrest patients using therapeutic hypothermia: "CODE ICE".

Out-of-hospital cardiac arrest is common and is associated with high mortality. The majority of in-hospital deaths from resuscitated victims of cardiac arrest are due to neurologic injury. Therapeutic hypothermia (TH) is now recommended for the management of comatose survivors of cardiac arrest. The rapid triage and standardized treatment of cardiac arrest patients can be challenging, and implementation of a TH program requires a multidisciplinary team approach. In 2010, we revised our institution's TH protocol, creating a "CODE ICE" pathway to improve the timely and coordinated care of cardiac arrest patients. As part of CODE ICE, we implemented comprehensive care pathways including measures such as a burst paging system and computerized physician support tools. "STEMI on ICE" integrates TH with our regional ST-elevation myocardial infarction network. Retrospective data were collected on 150 consecutive comatose cardiac arrest victims treated with TH (n = 82 pre-CODE ICE and n = 68 post-CODE ICE) from 2007 to 2011. After implementation of CODE ICE, the mean time to initiation of TH decreased from 306 ± 165 minutes to 196 ± 144 minutes (P < 0.001), and the time to target temperature decreased from 532 ± 214 minutes to 392 ± 215 minutes (P < 0.001). There was no significant change in survival or neurologic outcome at hospital discharge. Through the implementation of CODE ICE, we were able to reduce the time to initiation of TH and time to reach target temperature. Additional studies are needed to determine the effect of CODE ICE and similar pathways on clinical outcomes after cardiac arrest.

The potential of microelectrode arrays and microelectronics for biomedical research and diagnostics.

Planar microelectrode arrays (MEAs) are devices that can be used in biomedical and basic in vitro research to provide extracellular electrophysiological information about biological systems at high spatial and temporal resolution. Complementary metal oxide semiconductor (CMOS) is a technology with which MEAs can be produced on a microscale featuring high spatial resolution and excellent signal-to-noise characteristics. CMOS MEAs are specialized for the analysis of complete electrogenic cellular networks at the cellular or subcellular level in dissociated cultures, organotypic cultures, and acute tissue slices; they can also function as biosensors to detect biochemical events. Models of disease or the response of cellular networks to pharmacological compounds can be studied in vitro, allowing one to investigate pathologies, such as cardiac arrhythmias, memory impairment due to Alzheimer's disease, or vision impairment caused by ganglion cell degeneration in the retina.

The Bipolar Interactive Psychoeducation (BIPED) study: trial design and protocol.

BACKGROUND: Bipolar disorders affect between 3-5% of the population and are associated with considerable lifelong impairment. Since much of the morbidity associated with bipolar disorder is caused by recurrent depressive symptoms, which are often only poorly responsive to antidepressants, there is a need to develop alternative, non-pharmacological interventions. Psychoeducational interventions have emerged as promising long-term therapeutic options for bipolar disorder. METHODS/DESIGN: The study is an exploratory, individually randomised controlled trial. The intervention known as 'Beating Bipolar' is a psychoeducational programme which is delivered via a novel web-based system. We will recruit 100 patients with a diagnosis of DSM-IV bipolar disorder (including type I and type II) currently in clinical remission. The primary outcome is quality of life. This will be compared for those patients who have participated in the psychoeducational programme with those who received treatment as usual. Quality of life will be assessed immediately following the intervention as well as 10 months after randomisation. Secondary outcomes include current depressive and manic symptoms, number of episodes of depression and mania/hypomania experienced during the follow-up period, global functioning, functional impairment and insight. An assessment of costs and a process evaluation will also be conducted which will explore the feasibility and acceptability of the intervention as well as potential barriers to effectiveness. DISCUSSION: Bipolar disorder is common, under-recognised and often poorly managed. It is a chronic, life-long, relapsing condition which has an enormous impact on the individual and the economy. This trial will be the first to explore the effectiveness of a novel web-based psychoeducational intervention for patients with bipolar disorder which has potential to be easily rolled out to patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81375447.

Towards establishing a national colorectal cancer database: lessons learnt from Bio21 molecular medicine informatics model.

BACKGROUND: Collecting data regarding treatment and outcomes of patients with cancer, for both audit and research purposes, is a common but challenging goal. Modern technology promises greater ease and sophistication for data collection, linkage and analysis, but many traditional challenges remain. METHOD: Here we relate our experience of an initiative aimed at multicentre colorectal cancer data collection, that is, in collaboration with the Colorectal Surgical Society Australia and New Zealand, moving towards a national initiative. RESULTS: Initiated from a single site in Melbourne, using a range of data collection and linkage processes, and optimizing the use of modern technology, we have now implemented and sustained comprehensive and multidisciplinary data collection across multiple Victorian and interstate institutions. Specific challenges related to ethics and privacy, data accuracy and completeness and data ownership have been addressed and many lessons have been learnt. Multicentre audit and research queries can now be conducted with confidence that privacy, security and intellectual property issues are addressed. Research output, including many studies that were not previously possible, has informed a broad range of topics relevant to colorectal cancer. CONCLUSION: Multicentre and comprehensive data collection for colorectal cancer is achievable and sustainable and promises great benefit as an audit and research tool. Similar initiatives could be established for other tumour types.

Display of a maize cDNA library on baculovirus infected insect cells.

BACKGROUND: Maize is a good model system for cereal crop genetics and development because of its rich genetic heritage and well-characterized morphology. The sequencing of its genome is well advanced, and new technologies for efficient proteomic analysis are needed. Baculovirus expression systems have been used for the last twenty years to express in insect cells a wide variety of eukaryotic proteins that require complex folding or extensive posttranslational modification. More recently, baculovirus display technologies based on the expression of foreign sequences on the surface of Autographa californica (AcMNPV) have been developed. We investigated the potential of a display methodology for a cDNA library of maize young seedlings. RESULTS: We constructed a full-length cDNA library of young maize etiolated seedlings in the transfer vector pAcTMVSVG. The library contained a total of 2.5 x 10(5) independent clones. Expression of two known maize proteins, calreticulin and auxin binding protein (ABP1), was shown by western blot analysis of protein extracts from insect cells infected with the cDNA library. Display of the two proteins in infected insect cells was shown by selective biopanning using magnetic cell sorting and demonstrated proof of concept that the baculovirus maize cDNA display library could be used to identify and isolate proteins. CONCLUSION: The maize cDNA library constructed in this study relies on the novel technology of baculovirus display and is unique in currently published cDNA libraries. Produced to demonstrate proof of principle, it opens the way for the development of a eukaryotic in vivo display tool which would be ideally suited for rapid screening of the maize proteome for binding partners, such as proteins involved in hormone regulation or defence.

Antipsychotics and hyperprolactinaemia: clinical recommendations.

A group of international experts in psychiatry, medicine, toxicology and pharmacy assembled to undertake a critical examination of the currently available clinical guidance on hyperprolactinaemia. This paper summarises the group's collective views and provides a summary of the recommendations agreed by the consensus group to assist clinicians in the recognition, clinical assessment, investigation and management of elevated plasma prolactin levels in patients being treated for severe mental illness. It also deals with the special problems of particular populations, gives advice about information that should be provided to patients, and suggests a strategy for routine monitoring of prolactin. The recommendations are based upon the evidence contained in the supplement 'Hyperprolactinaemia in schizophrenia and bipolar disorder: Clinical Implications' (2008). The guidance contained in this article is not intended to replace national guidance (such as that of the National Institute of Clinical Excellence), however, it does provide additional detail that is unlikely to be covered in existing guidelines, and focuses on areas of uncertainty and disagreement. We hope it will add to the debate about this topic.

Presynaptic alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate [3H]d-aspartate release from rat frontal cortex in vitro.

The presynaptic nicotinic modulation of glutamatergic transmission in the CNS has been associated with activation of the alpha7 subtype of nicotinic acetylcholine receptor (nAChR) in sub-cortical regions, whereas in the frontal cortex, non-alpha7 nAChRs have been implicated. The aim of this investigation was to directly characterise nAChR-evoked release of excitatory amino acids from rat frontal cortex, by monitoring the release of [3H]D-aspartate from superfused synaptosomes or minces. Co-administration of a nAChR agonist with a depolarising stimulus enhanced [3H]D-aspartate release above the effect of depolarising agent alone. This enhancement was blocked by the nicotinic antagonist mecamylamine. Other experiments revealed that in the absence of a depolarising stimulus, the nAChR agonists nicotine, epibatidine and anatoxin-a could evoke the release of [3H]D-aspartate in a Ca2+- and concentration-dependant manner. Differential sensitivity to the alpha7- and beta2*-selective nAChR antagonists alpha-bungarotoxin (alpha-Bgt) and dihydro-beta-erythroidine (DHbetaE) implicated two nAChR subtypes (alpha7 and beta2*), and this was supported by using the subtype-selective agonists choline (10 mM; alpha7 selective, blocked by alpha-Bgt but not by DHbetaE) and 5-Iodo-A-85380 (10 nM; beta2*-selective, blocked by DHbetaE but not by alpha-Bgt). Immunocytochemistry showed that alpha-Bgt labelling was associated with structures immunopositive for vesicular glutamate transporters, in both frontal cortex sections and synaptosome preparations, supporting the presence of alpha7 nAChR on glutamatergic terminals in rat frontal cortex.

Preoperative chemotherapy and radiotherapy for locally advanced rectal cancer.

BACKGROUND: The adjuvant treatment of rectal cancer is a rapidly evolving field. The standard approach is a combination of chemotherapy and radiotherapy, with the optimal treatment combination and sequencing yet to be determined. Here, we report our early experience of preoperative chemotherapy and radiotherapy (CRT) in locally advanced rectal cancer at Radiation Oncology Victoria to determine its efficacy and the rate of sphincter preservation. METHODS: Sixty-nine patients (46 men and 23 women) with locally advanced rectal cancer (T3-4 or N1) were treated with preoperative CRT followed by surgical resection of disease. Chemotherapy consisted of either bolus or continuous venous infusion of 5-fluorouracil (5-FU). Radiotherapy to a dose of 45 Gy was delivered to the pelvis followed by a boost of 5.4-14.4 Gy in the majority of patients. Surgical resection was carried out 4-8 weeks following completion of preoperative CRT. Univariate and multivariate analyses were performed to examine variables that may influence local recurrence and overall survival rates. RESULTS: All patients underwent a complete macroscopic resection, including the three patients that had unrecognized distant metastases discovered at the time of operation. Only two patients had microscopic residual disease. Sphincter preservation was achieved in 16 of 25 patients who were thought to require an abdominoperineal resection. Tumour and/or nodal downstaging were achieved in 47 patients (68%), with a pathological complete response in 12 (17%). At a median follow up of 29 months post-surgery, five patients (7.2%) have developed a local recurrence. Overall 21 patients (30%) have progressed and 12 (18%) have died. Treatment-related toxicity was acceptable and there was no treatment-related mortality. There was no significant relationship found between the pathological response to treatment and any clinical endpoint. CONCLUSIONS: Our results confirm the high response rates and acceptable toxicity of preoperative treatment. Further studies are required to better define the impact of preoperative chemotherapy and radiotherapy on long-term outcomes.